Keywords

1 Introduction

Aging seems to be the only way to live longer!

Fascination with studying the biology of aging process has intensified only in the mid-twentieth century, as the growth of population of older adults is rapidly rising around the world and the economic cost of healthcare for elderly with chronic illnesses is becoming a significant national burden. With advanced aging, the likelihood of development of one or more significant medical illnesses in the elderly increases. However, the increased rate of population among healthy older individuals around the globe suggests that the aging process is not necessarily associated with illnesses. Older people can lead a healthy, active and productive life well beyond the standard age of retirement of 65–70 years.

Several clinical reports demonstrate that the risks for older adults to develop community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP) rise when various illnesses such as swallowing disorders, recurrent aspiration, cognitive impairment, malnutrition, alcoholism, obstructive lung disease, congestive heart failure, diabetes, renal disease or immunosuppressive therapy are also present [1,2,3,4,5,6,7,8]. Published guidelines by various health organizations have limitations for diagnosis and treatment of these aging health conditions. The issues are often complicated by patient’s capacity to make decision when professionals require to observe practices on mental capacity of the patients, consent issues, criteria for safe discharge of patients from different health centers and related variables [8,9,10,11,12,13,14,15,16,17]. The principal clinical options recommended for management of patients that are exposed with specific pathogens (e.g., staphylococcus aureus, gram-positive cocci, bacteria ) include steroid administration (e.g., glucocorticosteroid), antibiotic intervention, gas exchange and airway pressure control. Such clinical practices present limitations of frequencies, duration or combination therapies, to be effective for all older individuals in different settings [5, 9, 14,15,16,17]. Furthermore, prevention strategies including vaccination (e.g., flu, meningitis) or life style recommendations and management advice with alternative or complementary treatment procedures (e.g., saline nebulizer, granulocyte-colony stimulating factor , fluid intake, physiotherapy, nutrition) or palliative care often produce complications such as the follow-up after discharge from hospital for microbiological tests in patients with moderate or severe CAP [12,13,14,15,16,17].

Biologically, defects in in cellular immunity (T cell) and cytokine production (e.g., IFN-γ) are considered risk factors for the increased morbidity in older adults (mean age 75 years) that are exposed to infective viruses such as respiratory syncytial virus (RSV), when compared with younger (mean age 31 years) adults [16, 17]. It should also be noted that even the older individuals who have no evidence of any clinical diseases may be at greater risk for developing pneumonia due to skewed immune dynamics and alterations of microbial clearance associated with advancing in age [1,2,3,4,5,6, 12,13,14,15,16,17,18].

As noted in Chap. 1, according to a 2014 report by Mirror, Mirror [18], comparing health status and performance of general population of Americans with 11 other developed nations (Australia, Canada, France, Germany, Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom), “The United States health care system is the most expensive in the world”, but consistently shows that U.S.A ranks last and underperforms [18]. The reported health performance dimensions that USA consistently rated last included:

  1. (a)

    Health Quality: The indicators were effective care, safe care, coordinated care, and patient-centered care. “While there has been some improvement in recent years, lower scores on safe and coordinated care pull the overall U.S. quality score down”.

  2. (b)

    Health Access: Due to the absence of universal coverage, while patients ‘in the U.S. have rapid access to specialized health care services, … they are less likely to report rapid access to primary care than people in leading countries in the study.

  3. (c)

    Health Efficiency: On health performance, USA measures last on expenditures and administrative costs, as well as on administrative hassles and avoidable emergency room use and duplicative medical testing compared with other developed nations.

  4. (d)

    Health Equity : “Americans with below-average incomes were much more likely than their counterparts in other countries to report not visiting a physician when sick; not getting a recommended test, treatment, or follow-up care; or not filling a prescription or skipping doses when needed because of costs.”

  5. (e)

    Healthy Living: The Americans rank last overall with poor scores on all three indicators of healthy living …“mortality amenable to medical care, infant mortality, and healthy life expectancy at age 60. The U.S. and U.K. had much higher death rates in 2007 from conditions amenable to medical care than some of the other countries…”

Economic burden to the society, particularly with regard to cost of cancer care and therapy is becoming unsustainable in USA and other developed countries such as Japan and England [18, 19]. As detailed in Chaps. 5 and 6, cancer therapy and cost of care for patients in USA is the reason for almost half of the home foreclosures, while, the outcomes of claimed cancer ‘targeted’ therapies , ‘personalized’ or ‘precision’ medicine produced 90% (±5) failure rates for solid tumors [19,20,21,22].

In this chapter, the author attempted to extend her recently published hypotheses that the different health conditions, which increase the reported risks of community-acquired pneumonia (CAP) in older adults or other age-associated health conditions have shared biological features; and that oxidative stress (unresolved, sub-clinical or chronic inflammation) is the hallmark of nearly all chronic diseases including site-specific cancers .

In this effort, outlined analyses of major interrelated biological features including important knowledge gaps in understanding the age-associated illnesses, as well as, problems in managing the care for the elderly are provided in the following [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]:

  1. (a)

    Older adults are immune compromised to varying degrees;

  2. (b)

    The differently known age-associated illnesses have oxidative stress as interdependent common links that are manifested in vulnerable-susceptible tissue/organ systems as distinct diseases;

  3. (c)

    Oxidative stress or unresolved (sub-clinical, chronic) inflammation differentially influences the tissue-specific features (e.g., immune-responsive and immune-privileged tissues, insulin -dependent and insulin-independent tissues for glucose transport and metabolism ) that lead to the induction and manifestation of different diseases;

  4. (d)

    Special or shared biological features (complications) of full-blown disease that generally determine the outcomes of nearly all chronic diseases fall into three major interdependent categories, tissue necrosis, vascular complications and tissue growth;

  5. (e)

    Effective immunity (immune surveillance ) that is ‘friend’ for protecting the body against all harmful elements becomes ‘foe’ during aging and chronic inflammation (oxidative stress) and utilizes same molecular tools of inherent duality of immune and non-immune systems in favor of initiation and progression of chronic conditions in vulnerable tissues;

  6. (f)

    The majority of age-associated chronic illnesses are very likely preventable or correctable, if the scientific understanding of the biology of aging was focused on the maintenance of effective immunity (balancing the inherent tumoricidal vs tumorigenic properties of immune surveillance ), and caring for the elderly in hospital settings were significantly improved;

Detailed discussion of clinical or basic research on the individual chronic diseases is out of the scope of this book. Attempts were made to demonstrate that longevity and oxidative stress (unresolved, subclinical, persistent or chronic inflammation) are co-morbidity and co-mortality risk factors in the induction of nearly all age-associated chronic diseases such as neurodegenerative and autoimmune diseases , diabetes and cardiovascular complications, stroke, hypertension , Alzheimer’s , Parkinson’s, lupus, colitis , as well as, site-specific tissue growth, neoplasia, hyperplasia, cancer metastasis and angiogenesis .

2 Principals in Biology of Aging Process

Until a few decades ago and despite the development of numerous modern technologies for detection of hundreds and thousands of isolated molecular entities in the fields of OMICS (e.g., proteomics , genomics , lipidomics, metabolomics , glycomics ), little serious scientific efforts were invested for systematic understanding of the aging process, the immunosenescence and the initiation of age-associated chronic diseases . Numerous risk factors have been identified that predispose the elderly to several chronic diseases such as neurodegenerative and autoimmune diseases , asthma /emphysema and lower respiratory tract infections , Alzheimer’s , adult on-set diabetes and cardiovascular complications, Parkinson’s, osteoporosis and many site-specific cancers [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. However, the molecular or cellular bases of these health problems are yet to be integrated or understood sufficiently enough to achieve better outcomes for improving public health. Admittedly, a biological reason for the lack of progress in studying the interdependent events during the induction of age-associated health problems is the combined and complex extrinsic and intrinsic heterogeneities that are involved in the pathobiology of common illnesses.

To appreciate the complexity of the biology of aging and age-associated chronic diseases , the core principals that govern biological activities in eukaryotic cells are outlined in the following. It is important to note that from birth to death, the multicellular organism of the human body is subject to continued energy-requiring wear and tear processes to accommodate repairing and adaptation that are required for maintenance of health. Aging and weakened status and eventual loss of controlled wear and tear processes (regeneration, degeneration and recycling) are likely the bases for initiation and progression of diseases as well as death (details in Chap. 6) (Fig. 3.1) [56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]:

  1. (i)

    The body is a dynamic system of complex and highly interactive multiple organs, whose function continually evolves, from the conception and fetal growth all the way through life including the aging process.

  2. (ii)

    The proper functioning of organ systems involves a wide range of well-orchestrated and energy-dependent physical, mechanical, molecular and chemical signal transduction mechanisms involving genetic/epigenetic, enzymatic, metabolic and neuronal activities for the purpose of regeneration, degradation and turnover processes and survival. The highly regulated crosstalks occur continuously between and among organs, glands, tissues and cells of the skin, liver, kidney, lung, heart, stomach, eyes, bones, muscles, thymus, immune cells, vasculature , neuronal , and gastrointestinal tract.

  3. (iii)

    Among critical steps in sustenance of normal living cells are the proton pumping across the membrane and generation of differential acidity between cellular membrane and cytoplasm. Continued proton pumping and generated electricity is required for numerous routine cell activities such as lysosomal digestion and protein recycling , ion/solute transport, degradation of pathogen ’s structural proteins/lipids/genes for immune recognition/activation, as well as cellular proliferation. The extent of proton pumping provided through vascular and other cell membrane ATPases alter, to varying degrees, from the time of fetal growth and after birth, as well as during aging or disease processes including carcinogenesis. Agents that are foreign to the body as well as aging process and diseases can temporarily or permanently disturb the membrane effective potential of cell environmental pH causing skewed signal transduction and crosstalk between and among cells/tissues for achieving and controlling the required activities of the cells.

  4. (iv)

    Interactions and signal transductions between immune and non-immune tissue components (e.g., cells, organelles, proteins/enzymes, lipids, DNA/RNA) are amazingly successful complexes of turnover and regeneration processes with durations lasting from a fraction of seconds to several minutes; few days or months and even years. To achieve various crosstalks all types of cells and organ systems must follow biological rules of rhythmicity at different and precise levels. The links among physio-immune-neuronal-hormonal or pathological features of nearly all tissue/organ systems follow the control mechanisms of circadian rhythms (positive-negative response cycles). The circadian system is defined as a principal pacemaker in the suprachiasmatic nucleus circadian (SNC) in coordination with a number of peripheral circadian oscillators. Patho-physiological features of chronic diseases such as metabolic syndrome, site-specific cancers , diabetes and cardiovascular complications are very likely associated with disruptive conditions of certain components of the circadian cycle. The insufficient circadian rhythms could be the results of mutations of the clock genes, circadian control genes, or physiological and perhaps immunological deficiencies that lead to altered synchronization between SCN and other peripheral dual features of biological oscillators.

  5. (v)

    The various synchronization properties are defined as the natural positive and negative duality (oscillations) or biphasic events that are required for maintenance of health. In general, approximate duration of biological rhythms (collectively labeled as ‘effective acquisition time’) are classified into three major categories:

  1. (a)

    Ultradian, lasting seconds to several hours (e.g., neuronal and visual signal transduction , ion fluxes, hormonal release, enzymatic reactions, transporter activities, biosynthesis of receptor molecules , chromosomal repair activities, type 1 or immediate hypersensitivity responses),

  2. (b)

    Circadian, lasting approximately 24 h (e.g., skin turnover, melatonin, cellular and extracellular membrane component biosynthesis),

  3. (c)

    Infradian, also known as tidal or annual pathways, lasting more than a few days (e.g., biosynthesis and turnover of hemoglobin, mast cell sensitization and responses). Regeneration of complex organ systems (e.g., liver, lung or kidneys) may take a few years to be completed,

  1. (vi)

    Aging process itself is a dynamic phenomenon of biological regeneration and degeneration characteristic of all multicellular organisms with minor or major declines skewed/retarded in the biological switches. For example, aging process and altered hormonal and related activities lead to declines or accelerations (skewed) physiological activities (biological rearrangements) in organs/tissues (biological senescence). Aging process also induces minor or major changes in immune response dynamics within organ systems (immunosenescence). The age-induced altered natural biological and immunological activities, in general, lead to altered effectiveness of immune surveillance or the balance between tumoricidal vs. tumorigenic properties of immune system, weakening the body to effectively challenge toxicity of components that potentially threaten the body’s survival.

Fig. 3.1
figure 1

Schematic representation of maintenance of Yin-Yang (tumoricidal vs tumorigenic ) of acute inflammation in health (left panel) and induction of oxidative stress in alterations of intrinsic and extrinsic factors toward increased risk of chronic diseases during aging process (right panel). It represents that aging and oxidative stress increase risk of chronic diseases. Alterations or loss of mitochondrial function (mitophagy), ribosomal activities (autophagy), accumulation of oxidants (ROS/RNS), increased mutated genes (DNA/RNA) and immune suppression (changes in CMI/HI) lead to increased risk of asthma/emphysema, diabetes and cardiovascular diseases, stroke, Alzheimer’s, neurodegenerative or autoimmune diseases or cancer and angiogenesis) (Reproduced from Khatami Clin Trans Med 2016 [80]. All rights reserved)

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It is hypothesized that the overall control switches of the stimulating and inhibitory processes that follow the above rhythmic rules are larger version of the original definitions that the author proposed [30] for effective immunity , possessing 2 highly regulated and biologically opposing arms (biphasic or Yin and Yang ) mechanisms provided through acute inflammation (immune surveillance ) for maintenance of health.

In summary, maintenance of health depends on the inherently precise expression and regulations of energy-requiring positive and negative biological control switches (biological rhythms or clocks) between the local (host) and distant immune and non-immune (e.g., vasculature , metabolism neuroendocrine or neuro-physiological) systems [80].

The recently accepted adaptive origin of life is somewhat in contrast with the evolutionary theory of exclusion as traditionally known.

3 Biological Theories of Aging: Search for Common Link

In the last few decades, numerous biological theories of aging have been proposed to explain the mechanisms of aging process. To date, among the popular theories of aging are the genetic program theory, wear-and-tear theory, telomere theory, endocrine/hormonal theory, melatonin theory, DNA damage hypothesis, error catastrophe theory, the rate of living theory, mitochondrial theory , the nitric oxide hypothesis, the free radical and/or the oxidative stress theory, mitochondrial and immune/inflammation theory (reviewed in [45, 56, 61,62,63, 65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90]). These reports address and argue some of the challenges on the validity and pitfalls of documented theories that include isolated efforts to prevent diseases or slow down aging and prolong life, by means of food and nutrition intake, exercise and diet restrictions [47, 49, 58, 71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120].

As discussed in the following sections, the various aging theories , in all likelihood, are interdependent and the oxidative stress is the major influence on the intrinsic and extrinsic biological systems affecting the immune surveillance (immunity) that Burnet theorized over six decades ago [28]. Support for interdependence of the known theories of aging comes from the observations that age-induced alterations of hormonal, immunological, genomic functions are co-morbidity and co-mortality risk factors whose declines are accelerated by oxidative stress and accumulation of free radicals in tissues in the direction of initiation of nearly all age-associated chronic diseases (Figs. 3.1 and 3.2) [21,22,23,24,25,26, 80].

Fig. 3.2
figure 2

Schematic representation that longevity and oxidative stress are co-morbidity and co-mortality risk factors that would increase the risk of chronic illnesses. As depicted in the figure, chronic inflammation differentially influences the tissues that are immune-responsive or immune-privileged leading to a wide range of illnesses that are potentially interrelated. See text

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The following outlines the analyses of data on major interdependent biological dynamics in aging process based on reported theories with emphasis on the role of oxidative stress. The mechanisms of actions of immune disruptors and induction of chronic/unresolved inflammation are suggested as common links in the genesis of nearly all chronic illnesses and site-specific cancers [reviewed in 21,22,23,24,25,26, 31,32,33,34,35,36, 50, 80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150]:

  1. (a)

    Aging accompanies the atrophy or shrinkage of thymus followed by shortage of biosynthesis of stem cells , the giant manufacturer of immune cells. The shortage of stem cells often leads to altered/inefficient synthesis and response dynamics of innate and adaptive immune cells . The effects of aging on the immune system are widespread and extend from altered functions of the hematopoietic stem cells and lymphoid progenitors in the bone marrow and thymus to mature lymphocytes in secondary lymphoid organs. The combined changes result in a diminution of immune responsiveness in the elderly (immunosenescence);

  2. (b)

    The endocrine system and the function or levels of hormones (e.g., estrogen, insulin , testosterone, DHA) that play important roles in modulation of oxidative stress, metabolism and physiology of tissues alter in aging. Endocrine deficiencies impact the dynamics of immune responses;

  3. (c)

    Oxidative stress-induced altered chromosomal components and increased mutations of the genetics and epigenetics materials that damage the DNA/RNA and expression profiles and functions of proteins/enzymes, hormones , cytokines/chemokines or lipids influence tissue physiology and function;

  4. (d)

    Aging can cause impaired or insufficient transport properties of metabolites (e.g., glucose, myo-inositol, pyridoxine/pyridoxal phosphate, vitamin C), their receptors and cell surface molecules and loss of effectiveness in homeostasis of oxido-redox potential and bioenergetics in tissues (e.g., nuclear and membrane phosphorylation and dephosphorylation by kinases and phosphatases);

  5. (e)

    Accumulation of senescence cells and loss of effectiveness in protein/lipid recycling pathways involving intracellular organelles such as lysosomes, ER, Golgi apparatus and mitochondria and induction of pathological status in autophagy and mitophagy ;

  6. (f)

    Promotion of telomere attrition is an important contributing factor in aging;

  7. (g)

    Free radicals accumulation and induction of impaired circadian rhythmicity and cardiac output are among important factors in aging process;

While the importance of individual genetic makeup (intrinsic factor ) in longevity is logical, how the confounding extrinsic factors such as the interactions of oxidative stress and aging process lead to increased somatic mutations that would affect the regulations of biological clocks and chemical functions of organ systems in the direction of diseases are not understood. The degrees of interactions between intrinsic (innate) factors or the genetic makeup that influence the physiological behaviors of the organs/tissues (e.g., vasculature , metabolic, hormonal, neuronal and immune response pathways), combined with extrinsic factors (e.g., exposures to chemical, environmental, biological hazards, life styles) are likely to impose major impacts in aging process and the outcomes of age-associated chronic conditions (Fig. 3.2).

In 2008, the author defined that acute inflammation possesses 2 tightly regulated and biologically opposing arms (biphasic), termed Yin (tumoricidal , apoptosis ) and Yang (tumorigenic , wound healing ) properties of immunity. Yin and Yang control an elaborate and precise crosstalk between immune and non-immune (e.g., vasculature , neuroendocrine and metabolic pathways) systems to protect the body against all foreign elements that threatens the body’s survival [30, 80]. It was further hypothesized that chronic inflammation is a major risk factor underlying aging and age-related diseases [23,24,25,26,27, 30, 80]. Since 1998 at the National Cancer Institute (NCI ) a major goal of the author has been to promote the important roles that inflammation play in cancer biology. In the last decade, heavily funded projects and significant number of publications are devoted to fragmented proposed hypotheses on the role of inflammation in cancer research, immunotherapy and related network and conferences around the world. However, except for our ‘accidental’ discoveries that were established in 1980’s, little efforts have been invested to systematically understand the early events that occur between tissues and immune disruptors that alter immune dynamics in tissue toward multistep carcinogenesis ([21,22,23,24,25,26,27, 30, 31, 50,51,52,53,54,55,56,57,58,59,60, 80], submitted documents to NCI /NIH since 1998).

4 Free Radical Concept and Oxidative Stress Theory of Aging: Role of Mitochondria

Half a century ago, Harman [65] originally postulated that the free-radical theory of aging is the accumulation of the molecular damage in tissue caused by byproducts of the normal oxidative metabolism , called reactive oxygen species (ROS ). Harman further extended his theory and explained the role of mitochondria in aging process since mitochondria is the main source of generation of ROS and SODs [65, 66]. Since then, other studies following the discovery of detoxifying enzymes such as the superoxide dismutases (SODs), within cellular components and organelles (e.g., cytosol, mitochondria) that neutralize the superoxide anions; catalases and detection of the hydrogen peroxide (H2O2) provided credibility and support for the free-radical theory of aging [80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,265,113,114,115,116,117,118]. Understanding of the signaling pathways in aging that involve free radical theory largely comes from the investigations on the nematode Caenorhabditis elegans (C-elegans ) organism [99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116]. Analyses of reported data using this model address how reactive oxygen species (ROS) influence the aging process. Data demonstrate that over time ROS and/or oxidative stress accumulate some types of damage in specific targets such as the proteins, lipids, or nucleic acids contributing to the aging process. However, further analyses of such data on the oxidative biology of C. elegans show debates and controversies that ROS are not the toxic byproducts of the oxidative metabolism , since using anti-oxidant interventional therapies to alter the effects of accumulation of ROS remain inconclusive. It has been suggested that the overall rise in oxidative damage is not a major factor determining lifespan, due to duality of oxido-redux or rhythmic biology in organ systems that are capable of neutralizing the impact of ROS or other oxidants through effective function of anti-oxidants in healthy aging body. Furthermore, the notion that a general increase in oxidative stress does not limit lifespan in this model organism suggests that under stressful conditions, resistant to oxidative stress might be important to normal lifespan and reproduction in C-elegans , or other experimental model systems and human subjects.

In the last few decades many oxidants and enzymes have been identified that are not free radicals but, if not properly neutralized and removed by antioxidants and growth factors , they produce oxidative damage to tissues, perhaps participating in the loss of balance between the Yin and Yang (tumoricidal and tumorigenic ) properties of acute inflammation [21,22,23,24,25,26,27, 30,31,32,33,34,35,36, 80, 117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165]. Several studies demonstrate that the normal byproducts of cellular metabolism including the intermediates of mitochondrial respiration or the activities of oxidative enzymes (e.g., cytochrome P-450, NADPH oxidase, myeloperoxidases , NO synthase, glutathione peroxidase, or xanthine oxidases), generate highly reactive molecules with unpaired electrons or free radicals (e.g., ROS , RNS , superanions-HO−, peroxynitrile, H2O2, NADP+). The generation of oxidants are routinely neutralized by cellular antioxidants and scavengers of free radicals, agents that possess reductive capacity and protect tissue components from oxidative damage and maintenance of the oxido-reductive status of cells. Generation of normal amounts of ROS is required for routine regulation of cell functions, including apoptosis and proliferation that influence intracellular signaling pathways, gene expression, fragmentation of DNA, membrane lipid peroxidation and increased vulnerability of extracellular matrix to proteases. For example, hydroxyl ions (HO−) or O2− can interact and oxidize free iron (Fe+2, reduced form) or copper (Cu+) ions, or NO to their oxidized forms (e.g., Fe3+, Cu2+, or ONOO−) and thereby modify and regulate the function of specialized carrier proteins (e.g., ferritin) or availability of NO [21, 23, 25, 30,31,32,33,34,35,36,37,38, 46,47,48,49,50, 80, 86, 150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180]. Related information supports that oxidative stress induces activation of enzymes [e.g., NADPH oxidase, peroxisome proliferators-activated receptors (PPARs), pro-inflammatory mediators (e.g., IL-6, IL-10, TNF-α, PGs ] and alters redox state of binding proteins (e.g., Fos, c-jun, c-myc, beta actin), altered activities of genomic , chromosomal or epigenetic component, DNA/RNA/mRNA or telomere and telomerase activities that would lead to early abnormal genetic responses and hematopoietic activation [170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,255]. These changes are known to contribute to the induction of numerous mild or severe conditions such as, asthma , atheroma, emphysema , atherosclerosis, autoimmune and neurodegenerative diseases, hypertension , stroke, multiple sclerosis, arthritis, neurodegenerative diseases, diabetes or Alzheimer’s or carcinogenesis and angiogenesis . Furthermore, the extent of presence of energy-consuming peroxidation-induced extracellular membrane damage (e.g., activities of MMPs and expression of type IV collagenase or lipid peroxidation) may determine the extent of immune response profiles and chromosomal/genomic damage in tissues and the fate of tumor growth, metastasis and angiogenesis in susceptible tissues such as squamous and epithelial tissues in lung, prostate , colorectal , stomach or ovary [80, 163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270].

An overall review of data provide compelling evidence that the aging process is centrally regulated by a complex energy-requiring metabolic activity, cellular proliferation and differentiation, immune response crosstalk and autophagy for protein/lipid recycling events. Among several energy-driven pathways, the major complex processes involve 2 distinct forms of mammalian target of rapamycin (mTORC1 and mTORC2 ), an evolutionary conserved family of serine/threonine kinase and member of the family of phosphoinositide-3 kinase (PI3K ) related kinases (PIKK). The role of mTORC1 has been shown to engage with complexes such as NAD+ -dependent deacetylase enzymes, SIRT1 pathways and include mediation by ROS -induced activation of S6 kinase and H2O2 production for signal transduction and regulation of cell growth and proliferation involving the immune response crosstalk. Abnormal function of TOR contributes to the tissue hypertrophy and hyperactivity toward cellular damage and age-related health conditions. Furthermore, activation of TOR-dependent pathways seems to limit lifespan by accelerating age-related diseases even before the accumulation of ROS induces death (details in Chap. 6).

Several age-associated diseases (e.g., atherosclerosis, stroke, cardiovascular complications, adult diabetes, neurodegenerative diseases or site-specific cancers ) clearly are affected by increased oxidative stress. Oxidative stress inactivates or alters functions of critical enzymes (e.g., superoxide dismutases , catalase, glutathione peroxidase and glutathione reductase), intrinsic metabolites (e.g., uric acid, bilirubin, SH-proteins, glutathione ), extrinsic reducing agents (e.g., vitamins C, D, E, carotenoids, flavonoids) or other antioxidants , and metal chelating proteins that prevent Fenton and Haber-Weiss chemistry have been identified as potential contributors of age-associated diseases. The reported loss of numerous natural protective mechanisms that prevent cellular damages associated with chronic diseases strongly support that the oxidative damage theory play a key role in aging [21,22,23,24,25,26,27, 30, 80, 111,112,265,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146, 183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285].

The classic free radical theory of aging includes mitochondria-related specific processes of senescence. Age-associated generation of free radicals and accumulation of ROS are toxins to the mitochondrial function including induction of numerous mitochondrial DNA mutations and progressive reduction in energy output that are significantly below the required levels of body’s function. The reduced output energy from mitochondria implicated in a number of age-associated health conditions such as the loss of memory, hearing, vision, and stamina and tumorigenesis .

Increased damage by free radicals is linked to the impairments of mitochondrial function, which further alters inflammatory processes required for routine immune or tissue remodeling. The release of pro-inflammatory cytokines from DNA-damaged cells and dysfunctional mitochondria (mitophagy or mitotically arrested DNA) that exhibit the senescence-associated secretory phenotype (SASP) present several adverse effects including mutations of stem cells that reduce the capacity of tissue regeneration processes and induction of cancer stem cells and abnormal tissue growth. Senescence-associated secretory phenotype also could potentially be involved in antigen-load and chronic inflammation that would lead to necrosis and neurodegenerative diseases in immune-privileged tissues [21, 23, 26, 27, 30,31,32,33,34,35,36,37,38, 80, 100, 142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216].

Review of several excellent reports suggest that in the mitochondrial concept (mitohormesis theory) under normal metabolism , the production of ROS seems an important molecular signal that induce ‘hormetic’ effect by triggering stress resistance and longevity and induction of specific antioxidants in response to ROS . Combined aging process and cumulative effects of ROS are important factors in the impaired mitochondrial metabolism , oxidative phosphorylation and differential bioenergetics in cell that participate in altered dynamics of immunity and induction of chronic diseases processes. Among important known factors that are involved in the ROS -induced dysfunction of mitochondria (mitophagy ) are mutations of certain genes (mit mutants) such as clk-1, isp-1 or neu-6, involved in expression of enzymes (e.g., increased SOD and catalase activities, or hypoxia -inducible transcription factor-HIF-1 ), perhaps biological attempts to offset the damaging effects of a rise in tissue ROS levels. Furthermore, inhibition of mitochondrial respiration leads to altered mitochondrial protein folding response (e.g., UPRmito and increased hsp-6 expression). The uncoupling of respiration could disturb the integrity of mitochondrial architectural integrity, causing abnormalities in membrane composition (e.g., cardiolipin), effective bioenergetics and signals for production of anti-oxidants and expression of enzymes (e.g., SOD) that are required for effective metabolism and immunity of organ systems and life span (see Sect. 7 below).

The natural antioxidants within organ systems include several enzymes [e.g., superoxide dismutases (SODs ), NADP+ reductase or catalase], hydrophilic agents [e.g., glutathione (GSH), vitamin C, uric acid], lipophilic compounds (e.g., vitamin E, carotenoids, and bilirubin), mitochondrial thioredoxin and metal ions with electron transfer capacity such as Fe2 +, Cu+. These antioxidants are ubiquitously distributed within cytoplasm, mitochondria and/or extracellular tissue compartments throughout the body. Antioxidant enzymes such as SODs prevent formation of highly reactive free radicals such as ROS by readily accepting and scavenging the unpaired electrons and transferring or converting the oxidants to other electron accepting molecules. For example, SODs convert superoxide anion (free radical O2−) to the less aggressive oxidant H2O2, which is further removed by other antioxidant enzymes such as GSH peroxidase or catalase, involving other reducing metabolites such as GSH, NADPH, vitamins E or C (ascorbate, semidehydro-ascorbate) recycling pathways [21,22,23,24,25,26,27, 30, 40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65, 80, 101,102,103,104,105,106,107,108,109,110,111,112,265,113,114,115,116,117,118,119,120,121,122,123,124, 144, 155,156,157,158,159,160,161,162,163,164,165]. It is likely that neutralization of ROS by natural antioxidants would reduce/regulate activation of mTOR and related kinase pathways that are associated with tissue hypertrophy and growth.

Thus far, the recommended caloric restriction is the only known strategy tested to increase the life span in rodents and may also applies to primates, and presumably humans [95,96,97,98, 127, 128, 158]. However, potential health benefits of a number of antioxidants , vitamins (e.g., vit D, E, C), anti-inflammatory agents, or sulfhydryl-containing agents (e.g., asprin, Amifostine , isothiocyanate, mercaptoethanol , N-acethylcysteine or captopril ) and precursors of reduced glutathione on cellular redox-sensitive transcription factors (e.g., NF-kB), leukocyte adherence or ACE or mast cell stabilizers (e.g., Na-cromolyn) could also be important in delaying or preventing age-associated diseases including cancer ([21,22,23,24,25,26,27, 30, 51, 78,79,80, 91, 96, 101, 116, 130,131,132, 148] Khatami submitted documents to NCI /NIH, since 1998).

In brief, the ‘oxidative stress’ theory, also known as the ‘free radical’ theory seems to have stood the test of time, as this biological phenomenon has been the most broadly investigated topic in biology of aging. The tightly controlled concentrations of ROS and fluctuations/oscillations (negative-positive switches) of the tissue redox potentials are important mediators of signaling processes for inflammatory responses and metabolism in tissues. The ongoing controversies to the oxidative damage theory of aging using the experimental models of aging are, most likely, due to the enormous knowledge gaps and lack of systematic understanding of the age-associated altered molecular dynamics of oxidative stress during the progressive deterioration of feedback controls of the immunity; the giant umbrella of the immune cells, the neuro-endocrine and the metabolic networks that lead to increased somatic mutations in the genesis of molecular catastrophic errors and initiation of site-specific diseases [24,25,26,27,28,29,30, 33,34,35,36, 50, 80, 112,265,113,114,115,116,117,118,119,120,121,122,123,124, 148]. Insights into the mechanisms of accumulation of ROS and the redox status of tissue compartments and response dynamic contributions in aging require detailed bioenergetic studies that would enable scientists to accurately detect the initial interrelated biological processes. In all likelihood, the functional loss of neutralizing ROS factors is the result of a progressive pro-oxidizing shift in the redox state of the cells during aging. This would lead to over-oxidation of the redox-sensitive proteins and consequently the disruption of redox-regulated signaling mechanisms.

5 Genomic Theory of Aging

Biological aging and tendency to decay the ordered systems into general disorder applies to all body’s cellular and molecular networks, including DNA and chromosomal damage [e.g., depurination and depyrimidation at normal acidity or temperature] that often lead to injury by water nucleophillic properties that could alter structural integrity and function of genetic, epigenetic and influence expression of proteins/enzymes as well as recycling pathways. Several elegant studies demonstrate that normal tissue metabolism including mitochondrial oxidative phosphorylation are associated with DNA mutations at the rate of about 10,000 bases/cell/day (for depurination or depyrimidation), or an average of 100 bases/cell/day (for cytosine deamination) that involve hydroxyl radical-mediated oxidative damage and altered immune response crosstalk among organ/tissues [168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237]. Normal aging process causes changes in the features of chromosomal function, including the shortening of telomere and expression of related proteins and enzymes that are required for maintenance of regeneration as well as degeneration pathways for nearly all activities of tissue components [30, 80, 172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197].

To maintain health and effective immunity throughout life, correction of generation of genetic errors and mismatches, require routine and simultaneous molecular repair pathways involving biological and immunological pathways of protein expression and recycling/regeneration processes or replication/repair of DNA/RNA molecules and nuclear components [80, 175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229]. The DNA repair mechanisms by AP Pol β base replacement (base excision repair BER) and related repair enzymes occasionally lead to base pair excision or modifications and rearrangements of one strand of DNA (mismatch repair) while the second strand remains as template for zip or fork replication. The process of fork replication on one strand seems to provide temporary vulnerability causing potential increased damage to DNA before the natural double-stranded DNA is repaired. The accumulation of mismatched or modified and unprocessed DNA bases would induce altered molecular signals for repair mechanisms including protein kinase signaling pathways leading to destabilization of recombination pathways during the loss of multi-potency of mesenchymal stromal cells and dysregulation of crosstalk in immune and non-immune pathways that could lead to the multistep chronic diseases such as epilepsy, bone and pulmonary diseases and cancer [30, 80, 168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191, 205,206,207, 213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229, 231,232,233,234,235,236,237]. It is suggested that accumulation of senescent cells with features of inactive/suppressed DNA/RNA or chromosomal activities present additional burden (antigen-load ) to organ systems for clearance and recycling pathways as potential contributing factors in aging.

Among the many factors involved in chromosomal and DNA damage, in the course of normal cellular metabolism , are oxidative damage to DNA during mitochondrial respiration , immune cell maturation and responses toward stimuli and exogenous factors (e.g., exposure to UV radiation or perhaps carcinogens), as well as cellular DNA synthesis during cell cycle transit [30, 80, 150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215, 228, 229]. During cellular DNA synthesis the damaged DNA is often magnified through slow process of replacement of an excised base and base pairing excision in the G1 phase (nicks) that may cause collapsed forks preventing correct replication forks into DNA double strand, leading to further large deletions and chromosomal damage and deficiencies in cell cycle progression and checkpoints (ATR protein kinase ) and fork stability. Therefore, the normal DNA replication processes, over time, create sufficient damage to DNA to cause stem and progenitor cell attrition and deplete tissue regeneration capacity leading to accelerated or premature decline in tissues renewal capacity of stem and progenitor cell fates that influence senescence and apoptosis and increased risks for onset of age-associated chronic diseases . It is also important to note that as is the case for immune response activities, nucleotide biosynthesis and related DNA/RNA repair pathways are ATP -dependent and require efficient mitochondrial integrity [30, 80, 159, 167, 171,172,173,174,175,176,177,178, 206, 207, 210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225, 228, 232].

Deficiencies in genome maintenance are associated with various aspects of premature aging in genetically modified animal models and in humans. Human specific genetic diseases featured by Werner syndrome , Cockayne syndrome , trichothiodystrophy , dyskeratosis congenital , and ataxia-telangiectasia , as well as age-associated conditions such as graying hair, alopecia , hyphosis, osteoporosis, and impaired tissue regeneration, have been reported in mouse models of aging in which targeted mutations have been generated in DNA damage response (DDR) regulators caused by mutation of genes involved in the efficient repair of DNA damage or the cell cycle regulatory response molecular patterns [165,166,167,168,169,170,171,172,173,174,175, 204]. Loss of stem and progenitor cells attrition and tissue homeostasis including impaired genome regenerative capacity in adult stem cells have been proposed as the general organismal decline in aging [30, 80, 172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187, 206, 207, 214, 219,220,221,222].

It is noteworthy, that only in the last decade, the decision makers in the cancer community have come to accept and appreciate that inflammation is a precancerous state of cells that initiates adaptive changes in epigenetic structures resulting in accumulation of genetic errors and impairments of regulation of gene expression in multistep carcinogenesis [25, 26, 159, 166,167,168,169,170,171,172, 200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229]. Epigenetics and post-mitotic modification events of gene expression pathways (e.g., DNA methylation, methylated DNA binding proteins, histone modification-related enzymes, microRNAs) or telomere -telomerase pathways are sensitive to immune dysfunction and oxidative stress [21,22,23,24,25,26,27, 30, 38,39,40,41,42,43,44, 48, 50,51,52,53,54,55,56, 73, 80, 135,136,137, 143, 171, 178, 255, 280, 282].

5.1 Role of Hyperactivation of Suppressor Gene Pathways in Aging

As described above, the process of restarting DNA replication forks and preventing collapse require 50 different genes during the complex multistage processes of DNA homologous recombination such as double-strand break recognition, strand invasion and space-‘holiday’ junction resolution. Defects in any steps of these molecular sequences could influence mutagenic types of repair processes and accumulation of DNA damage at bridge-breakage fusion cycles during the chromosomal translocations.

Analyses of relevant data demonstrate that aging and oxidative stress, to varying degrees, increase the genetic mutations at multiple locations leading to inactivation or defective function of suppressor gene molecules (e.g., p25, p35, p38, or p53 ) and increased instabilities in somatic maintenance and repair, proliferative control of gene expression as well as misguided expression of apoptosis or wound healing mediators [172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229]. The increased genetic mutations could also damage chromosomal contents and alter DNA methylation (hypo-, and hypermethylation) causing defects in cell contact inhibition and cell cycle regulation such as cyclin-dependent kinases (e.g., ser-thr kinases -cdks ) , telomere dysfunction or shortening as well as epigenetic and posttranslational events. A specific example of the role of suppressor genes mutations in senescence is the role of p38 pathways. The inactivation or mutation of P38 mitogen-activated protein kinase (MAPK ) that are involved in regulation of extracellular-signal regulated kinase (ERK ), c-Jun N-terminal kinase (JNK) could lead to enhanced cellular transformation and disruption in the induction of senescence that follows tumor growth. Furthermore, impaired DNA methylation of CpG islands, important molecular checkpoints in gene expression pathways influence carcinogenesis, inflammation and viral infection [21, 31, 92, 170, 178, 180, 181, 201, 202, 212,213,214,215,216,217,218,219,220,221,222,223,224,225,226, 237].

6 Immunosenescence Theory : Connecting the Dots with Oxidative Stress -Skewed Dynamics of Immunity in Aging

Immunoscenescence is the results of age-induced readjustment and/or remodeling of the immune cell dynamics, combined with age-associated physiological rearrangements and altered hormonal and metabolic changes (biological senescence). Immunoscencence-induced remodeling of immune system includes minor or major alterations in innate and adaptive immune cells and bone changes in the activities of bone morphogenesis and remodeling and initiation of disease processes [21,22,23,24,25,26,27,28,29,30, 33,34,35,36, 38,39,40,41,42,43,44,45, 48, 50,51,52,53,54,55,56, 80, 239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259, 284, 308,309,310].

A clinical feature of immunosenescence is the development of hyper-, or hypo-sensitivity reactions toward new antigen challenges and/or self-antigens and the observed increased allergies or autoimmune diseases in older adults. The immune dysfunction results from cumulative impairments in the complex network of cellular and humoral interactions of the critical cells in the immune system, including the dendritic, natural killer and mast cells, macrophages , B and T cell subpopulations (e.g., Th1/Th2 cells or B memory cell). Aging response to inflammation is cell and humoral mediated pathways (CMI , HI ), with active participation of nearly all other components of organ systems (e.g., vascular, metabolic, neuronal and hormonal pathways). Furthermore, the protective roles of immune responses (immune surveillance ) depend on the ability of immune cells to generate and retain ‘memory cells’ to recognize and respond in an accelerated defensive manner to pathogen exposures. The aging body generally retains immunity against previously encountered pathogens . However, components of immunologic memory show skewed responses toward new stimuli (pathogens or carcinogens) [21,22,23,24,25,26,27, 30, 41, 50, 80, 242,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,266,267,268,269,270,271,272,273,283, 311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355].

In general, aging causes minor or major alterations in the response ability of APCs to present antigen to the resting/naïve T cells (T0). The changes are likely due to the proposed altered balance between tumoricidal vs tumorigenic (Yin-Yang ) properties of immune response dynamics, or the loss of homeostasis of oxido-redox potential of immune and non-immune cells. Depending on the tissue immune cell composition and vulnerability toward oxidative stress, the loss of Yin-Yang balance could result in untimely maturation or polarity of APCs such as changes in DCs (DC1/DC2 ratios), granulation and degranulation of MCs (MCs-‘leaky’ or TAMC) and/or macrophage (M1/M2 or TAM) phenotype population. The altered response dynamics of APCs , could further contribute to the impaired inflammatory signals in maturation, migration or recruitment and infiltration of other inflammatory cells and/or defects in communications with adaptive T or B cells . Data on aging provide evidence that the dysfunction of humoral response profiles associated with changes in expression of antibody profiles (e.g., IgG , IgE , IgM, IgA and isotypes ) are, in part, due to decreases in Th1 (tumoricidal ) response ability to provide appropriate crosstalk through co-stimulatory molecules, expression of cytokines and/or effective production of immunoglobulins. Aging is also associated with defects in T cell responses to viral infections . As detailed below, defects in cellular and humoral immunity (CMI , HI ) are likely the result of increased morbidity in older adults with infective viruses (e.g., respiratory syncytial virus , RSV) or increased chronic allergies (e.g., asthma , emphysema ).

6.1 Immune Competency in Aging: Role of Antigen Presenting Cells (APCs ) in Immunosenescence

In general, advance aging appears to cause decreases in both non-immune and immune defenses, although many aspects of immunity remain robust in centenarians. A growing body of evidence supports the notion that aging- and oxidative stress-induced impaired function of antigen presenting cells (APCs) could alter response profiles of adoptive immunity, which collectively cause retardation of the dynamics of crosstalk in non-immune (e.g., vasculature , neuronal , hormonal and metabolic) pathways in the direction of initiation and manifestation of chronic health problems. For example, APCs are responsible for recognition, uptake, processing and presentation of processed/digested antigens/pathogens to the antigen-specific receptor molecules (epitopes) of major histocompatibility complexes (MHC , MHC I and II ) on T cells [21, 30, 80, 205,206,207, 221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,345].

The intrinsic processes of T cell activation (adaptive immunity) require interactions between T cells and APCs . In an acute inflammation , APCs and the expression of specific cytokines and mediators initiate and determine the outcomes of effector T cell responses (pharmacological effects) and the maintenance of balance in dual properties of Th1/Th2 and cytokine expression profiles [21,22,23,24,25,26,27, 30, 50, 80, 217, 336, 348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369].

In general, innate immune cells express invariant receptors, as opposed to adaptive immune cells, which express rearranged receptors for a wide range of processed antigens presented by APCs. Among major antigen presenting cells are the dendritic cells (DCs , the most professional APCs ), and macrophages (MΦs , also professional phagocytes /monocytes). Activation of inflammatory cells (e.g., DCs , MΦs , MCs, eosinophils /Eos) and the production of diverse pro-inflammatory signals, cytokines and chemokines initiate crosstalk between innate and acquired immune response systems for generation of memory B cells and humoral response mechanisms. The APCs play key roles in protection of epithelium and mucosal surfaces through specific receptors that recognize, capture and ferry specific moieties of pathogens such as bacteria , viruses or other microorganisms such as mannose-rich glycoproteins or lipopolysaccharides (LPS ). APCs are able to produce specific anti-bacterial peptides/cytokines or reactive oxygen species and neurotoxins that kill/destroy the infective pathogens or tumor cells. As a result, APCs generate various pro-inflammatory (apoptotic or tumoricidal ) mediators that interact with and upregulate their counterparts in adaptive immune cells for acquired immune responses and activation or recruitment of other inflammatory cells [21, 80, 217, 265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285, 336, 348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369] (see Chap. 6).

With advancing age, naïve T cell population gradually decline while memory cells become predominant and tend to cause skewed (hypo-, or hyper-) responsiveness toward stimuli as bases for the increased prevalence of age-associated conditions such as asthma , emphysema , ocular and skin allergies, arthritis or neurodegenerative and autoimmune diseases or cell growth [21,22,23,24,25,, 80, 280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297, 370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388]. Older adults often demonstrate higher allergen sensitization as evaluated by total IgE levels. Furthermore, age-related T cell immune deficiency is preceded by intrinsic changes within bone marrow stem cells and the involution of the thymus. Bone marrow stem cells show decreased affinity for the thymic stroma . Atrophy of the thymus is associated with loss of thymic hormone and alterations in T cell function as well as changes in metabolic activities of the tissues as integrated factors in diseases processes [21, 80, 81, 289,290,291,292,293,294, 370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390] (see Chap. 6).

It is noteworthy that the collective alterations in anti-inflammatory and bioenergetics of aging (e.g., changes in hormonal, metabolic, physiological and mitochondrial activities) accompanied by sustained oxidative stress could induce expression or co-expression of mismatched growth and apoptotic factors in susceptible tissues. The extra caloric intake may additionally disturb the feedback controls of metabolism in tissues in the direction of growth promotion and induction of site-specific cancers . Suggestions that caloric restriction and exercise would delay the age-related declines of physiological function and chronic illnesses and promote healthy aging are biologically logical as obesity and extra caloric intake may additionally impair the oxido-redox balance in tissue in favor of growth promotion (see below) [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64, 78,79,80, 97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,265,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138, 155, 158, 176, 247,248,249,250,251,252].

6.2 Multipotent Hematopoietic Stem Cells

Cells of the immune system are constantly renewed and supplied by the giant manufacturer of hematopoietic multipotent stem cells. Well documented data demonstrate that with aging the thymus involutes and the supply of naïve T cells gradually falls causing a reduction in the overall renewal capacity of stem cell. The critical deficits that occur in stem cells , particularly changes in T cells, are termed immunosenescence. The inefficiency of immune system to defend against new pathogens or cancerous cells and the increased incidence of autoimmune, inflammatory and infectious diseases during the aging process is recognized in the last few decades (Fig. 3.3) [21,22,23,24,25,26,27, 30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56, 178, 193,194,195,196,197,198,199,200, 221, 243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345]. For example, the proliferative activity of bone marrow peaks in middle age and then gradually decreases in older individuals, a phenomenon perhaps associated with increased apoptosis in aging. Consistent with these observations, CD 34+ stem cells mobilize less effectively in the elderly when compared to younger donors. Moreover, thymic involution, decreased lymphopoiesis along with reduction in the ability of marrow stroma to support lymphopoiesis have been reported in aging. Aging also causes cumulative expansion of memory cells and increased expression/ co-expression of apoptotic (Yin) and wound healing (Yang) mediators. These changes alter CMI and HI immune competence in aging [21, 24, 30, 31, 80, 178, 193, 199, 200, 219, 288,289,290,291,292,293,294,295,296,297,298,299,300,301,337, 459, 489].

The changes in multipotent hematopoietic stem cell population originate from alterations of bone marrow remodeling and regenerative processes as well as thymic and spleen T-lineage committed to stem cell biosynthesis and function. The features of immunosenescence are the following three primary changes in hematopoietic (innate and adaptive) immune cells that result in skewed immune response dynamics of CMI and HI accompanied by altered vasculature , metabolic and physiological activities in organs/tissues [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50, 80, 186, 200, 226, 244,245,246,247,248,249,250,251,252,253,254, 264,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497,498,499,500,501,502,503,504,505,506,507,508,509,510,511,512,513,514,515,516,517,518,519,520,521,522]:

  1. (a)

    A decline in the number of naïve cells due to diminished thymopoiesis;

  2. (b)

    An increase in the number of memory cells resulting in abnormal expression of cytokines/chemokines , other mediators or antibodies and mucosal secretion activities;

  3. (c)

    Dysfunctional accumulation of activated effector cells , limited mutations of activated effector cells and limited T cell repertoire occupying T cell space.

Upon infection , adoptive immunity provides protection through three basic phases of recognition, activation/effector and memory. The age-induced immune dysfunction may occur at any of these phases, particularly in the recognition phase where the immune response alterations are attributed to intrinsic B cell numerous molecular defects including skewed antigen presentation, mucosal secretion, reduced co-stimulation, antibody profiles, repertoire constrictions, or a combination of colonotypic immune responses as features of immunosenescence [21,22,23,24,25,26,27, 30, 37,38,39,40,41,42,43,44,45,46,47,48,49,50, 80, 186, 200, 226, 266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463].

As schematically represented in Fig. 3.3, myeloid cells, originated from megakaryocytes express a number of cytokines and receptor molecules with various functions in the genesis of monocytes (MΦs ) or granulocytes. There are at least 24 different immune cell types with distinct genetic profiling (at least 155 reported genes). They include innate and adaptive subpopulations/phenotypes, present in resting/normal (unstimulated) status or present distinct activities under a wide range of acute or chronic inflammatory responses or immunosenescence. Different immune cell phenotypes including platelets, innate and adaptive cells inherit expression of many cytokines and chemokines and receptor molecules with shared, overlapping/compensating or distinct features under specific conditions to main the body’s health [21,22,23,24, 31, 80, 147,148,149,150,151,152,153,154,155]. During antigen processing, the major functions of APCs are outlined below:

  1. (d)

    Expression of receptor/ligands and surface molecules, such as toll-like receptors (TLRs , IL types), surface molecules (over 100 proteins, such as CD40/CD40L, CD22, CD73), cytokines such as tumor necrosis factor superfamily (22 molecular expression entities), complement cascade (at least 12 reported genetic profiles). The expression of these factors requires them to recognize and bind pathogens or pathogen -processed structures for presentation to other immune cells or responses from non-immune cells;

  2. (e)

    Expression of innate cell-like (invariant) receptors (e.g., from platelets) for ingestion and destruction of microbiomes and prevention (termination) of pathogenicity;

  3. (f)

    Release of molecular signals to communicate with other immune or non-immune cells in the tissue microenvironment or at distance to facilitate inflammatory conditions;

  4. (g)

    Contribution to signaling molecular responses, facilitating polarization , differentiation and growth of other cells during apoptosis or wound healing or tissue repair and remodeling;

Fig. 3.3
figure 3

Schematic representation of stem cells as the giant manufacturer (pluripotent cells) of hematopoietic immune cells. As depicted, growth and differentiation of each immune cell is regulated by induction of expression of special or shared mediators, cytokines, chemokines , growth and factors. See text

Full size image

Therefore, the proper function of stem cells seems to be a key to healthy aging for making the body resistance to oxidative stress and delayed on-set of chronic diseases. However, longevity and the rate of functional capacities of organ systems and susceptibility to disabling diseases vary in individuals, perhaps due to a combination of genetics, immunological or biological factors as well as the frequency of exposure to diverse environmental hazards .

6.3 Cytokine/Chemokine Dynamics: Role of Decoy Receptors in Control of Acute or Chronic Inflammation in Health and Diseases

Pro- and anti-inflammatory signals from activated immune and non-immune cells regulate the levels and efficiency of inflammatory cytokine receptor coupling in a variety of inflammatory conditions to maintain the balance between Yin and Yang of immune surveillance or the control of immunity.

A major feature in the biology of immune system in aging is upregulation of inflammatory responses that seems detrimental to longevity . Data on age-dependent increased expression of several cytokines such as IL-2, IFN-γ, TNF-α (identified as Type 1), or IL-4, IL-6, IL-10 (identified as Type 2) that influence T cells, particularly CD8+ subset of effector/cytotoxic and memory cells memory cells in chronic inflammatory state and inability to fight viral infections in aging are not understood and often confusing [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41, 80, 134,135,136,137,138, 203,204,205,206,207, 238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264]. Detailed analyses of several reports, however, support the author’s recent hypotheses that loss of balance between Yin (pro-inflammatory ) and Yang (anti-inflammatory) processes of acute inflammation is the major force in the induction of chronic state of unresolved inflammation. In all likelihood, oxidative stress and aging process lay a foundation for persistent viral infections by EBV and CMV or the induction of other illnesses such as hypertension , neurological diseases, cardiovascular problems as well as site-specific cancers . In other words, aging and persistent viral infection induce chronic antigenic stimulation status (antigen-load , oxidative stress) and generate modifications of CD8+ subsets and inability to clear/resolve antigen-(infection)-induced activation of immune dynamics. Furthermore, age-dependent expansions of CD-8 + CD28- T cells, and co-expression of pro-inflammatory cytokines including CMV-epitope specific cells, underline the importance of chronic antigenic stimulation in the pathogenesis of immunological alterations that could favor the appearance of pathologies (e.g., arteriosclerosis, dementia, osteoporosis, cardiovascular complications, cancer), all of which share aspects of inflammatory components [21,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55, 68, 80, 266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286].

Further analyses of data demonstrate that stimuli-induced expression of pro-inflammatory cytokines and enzymes (e.g., IL-1, IL-6, IL-8, ΤΝF−α, M−CSF, GM-CSF , eotaxin, histamine, PGs , LTs, heparin, chymase , tryptase ) from activated resident (local) and/or recruited inflammatory cells, contribute to the amplification and progression of responses. The required signals to destroy the pathogens are often generated in part, by increasing the local concentrations of pro-inflammatory mediators produced by resident inflammatory cells or by producing additional cytokines or mediators (e.g., ROS /RNS , TGF-β ) from infiltrated macrophages , platelets or complement activation to accomplish a function (e.g., removal of an irritant or lysing of an infectious agent).

It appears that the major bases for age-associated persistent (chronic/unresolved) inflammatory status in the induction of chronic health conditions fall into two principal categories:

  1. 1.

    Loss of vascular integrity and function (vascular toning), further facilitated by skewed metabolic responses and impaired immune signals- resulting in increased vascular permeability and changes in the balance between angiogeneic and anti-angiogenic factors;

  2. 2.

    Impaired balance in the oxido-redox potentials or bioenergetic features in tissues/organ systems, as the principal loss of protective mechanisms of body’s health;

During an inflammatory response, the decoy receptors seem to function as control switches or checkpoints (feedback mechanisms) that simultaneously initiate the termination processes (Yang, wound healing ) following the Yin events (Fig. 3.4).

Fig. 3.4
figure 4

Schematic representation of interdependent roles of inflammatory cytokines during tissue stimulation in acute or chronic inflammatory conditions. See text

Full size image

Decoy receptor molecules are agonist-binding proteins that sequester inflammatory cytokines and signaling receptor components during termination or control of self-terminating acute inflammation . The cytokine receptor dual function (decoy behavior) was originally formulated for IL-1 and IL II receptors. Decoy receptors are structurally incapable of participating in signaling receptor complexes. However, they are able to sequester ligands that have subsequently been identified for IL-8, a member of the IL-1 family, and the TNFR superfamily (e.g., osteoprotegerin) [19,20,21,22,23,24,25,26,27,28,29,30, 80, 227, 250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266, 286,287,288, 297, 298, 303,304,305,306,307,308,309,310,311]. An example of extensively studied cytokine and decoy receptor function that is involved in the multistep carcinogenesis is tumor necrosis factor-alpha (TNF-α), a cysteine- rich cytokine and its receptor molecules (TNFR-1, TNF-Rp55, TNF-Rp75). The TNFRs act as transponders of TNF by receiving and transmitting signals that trigger inflammatory responses. The TNFR signaling mediates several biologically different functions during Yin and Yang of acute inflammation (programmed cell death ) for maintenance of tissue homeostasis and elimination of host cells with damaged DNA. Environmental or chemical stimuli (exogenous or endogenous) can trigger the synthesis and production of TNF-|α and its receptor molecules in a variety of cell types [e.g., MΦs , T cells (Th1, Th2), DCs , MCs or keratinocytes]. TNFR also has proliferative capabilities for growth of fibroblasts or thymocytes and induction of expression of superoxide dismutases to terminate acute inflammation (Yang), likely through expression of decoy receptor molecules (e.g., TNFdr). Other decoy receptors that participate in termination event of inflammation (Yang response) or proliferation of other immune or non-immune cells and cancer growth and angiogenesis , include receptor molecules for MCSF, iNO, PGE2 and/or histamine (released from ‘leaky MCs into tissue microenvironment, independent from IgE -fcεR binding) [21,22,23,24,25,26,27, 80, 200, 227, 265,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,266,267,268,269,270, 287,288,289,290,291,292,293] (see Chap. 6).

In brief, the expression of apoptotic or pro-inflammatory mediators (Yin events) has two distinct features:

  1. (a)

    Activation-induced cell death (AICD), which is a specific but ‘peculiar’ complex immune response dynamics for eliminating useless/excess lymphocytes that are produced during clonal expansion as a response to tissue antigenic stimulation;

  2. (b)

    Damaged-induced cell death (DICD), which is a more generalized immune response to a variety of cellular insults, particularly oxidative metabolism , biological byproducts and autophagy /mitophagy function in tissues;

Antigenic-load and the presence of pro-inflammatory status in aging process are associated with subtle remodeling on the functions of apoptotic processes in AICD and DICD. Other minor or major changes in immune cell function (e.g., changes in DCs and MΦs , MCs, NKs functions, or T- and B- cell response profiles) including induction of decoy receptor molecules , are likely to contribute to the unresolved inflammation and age-induced immunosenescence and initiation of chronic diseases [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44, 50,51,52,53,54,55,56,57,58,59,60, 80, 226, 240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298].

Accumulation of free radicals (e.g., ROS , RNS , ROO− ) signals that the status of oxidative-reductive potentials in tissue is imbalanced. Since stimuli-induced acute inflammatory responses are initiated through expression of danger molecules or the signaling receptors (e.g., TLRs , TNFR ), long-standing inflammatory conditions (oxidative stress) or the loss of effective defense could also be through altered signals of decoy receptor molecules to control acute inflammation . Under-, or over-expression of decoy receptor signaling could influence the activities of tissue components, such as vasculature integrity; shifts in the ratios of tissue oxidative-reductive status and altered synthesis of cell phenotypes (e.g., changes in M1/M2/TAM or DC1/DC2) that would lead to tissue growth-arrest or growth-promotion, or altered tumoricidal vs. tumorigenic ratios of immune cells (Figs. 3.3 and 3.4).

6.4 Role of Natural Killer Cells in Aging: Skewed Cytotoxicity

Natural killer (NKs ) cells have important and diverse functions within innate immunity as first line of defense. Recent studies demonstrate critical roles for NKs in reproduction and the most abundant cells (50–70%) at the maternal/fetal interface for induction of angiogenesis through specific MHC molecules. They also participate in control of adaptive immune cells and memory responses [21, 305, 312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328]. While the absolute number of NK cells, and the IFN-γ production and phagocytosis are increased in aging individuals, the NK-cell cytotoxicity on a ‘per-cell’ basis and the response to IL-2 is impaired. Age-associated increases in NK cells and in T cells expressing NK receptors was suggested to play a beneficiary role in immunosenescence and these effectors might blunt the growth of neoplastic cells in older individuals.

In the innate immune system, the levels of cytotoxic activities of natural killer (NK) cells has been shown to play critical roles in inhibiting tumor growth and metastasis in a number of studies. However, whether the inherent dual roles NKs (mature vs immature phenotypes) of immune surveillance is skewed during aging or carcinogenesis and metastasis are not well understood. Analyses of recent data suggest that cytotoxicity of human NKs and the presence of CD56 for lysing infected cells or oncogenically transformed cells may be altered by growth factors and membrane proteins such as human aspartyl-β-hydroxylase (HAAH), a member of the α-ketoglutarate-dependent 2,3 dioxygenase family that hydroxylates epidermal growth factor (EGF )-like domain in transformation-associated proteins [21, 305, 312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328].

Under certain inflammatory conditions, NKs may be considered as humoral as well as, cellular elements of the immune system for initiating crosstalk between innate and acquired/adoptive immunity through activation of vascular components. Some of the critical deficits in immunosenescence occur in stem cells and NKs , particularly, causing changes in T cell subpopulations that underlie the functional deficits of aging and extractable recovery from therapy [21, 80, 305, 312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328].

A number of reports show there are three primary changes in NKs -T cell function in aging:

  1. (a)

    Decline in the number of naïve cells due to diminished thymopoiesis;

  2. (b)

    Increased number of memory cells resulting in increased cytokine production;

  3. (c)

    Dysfunctional accumulation of activated effector cells of limited T cell mutation and skewed T cell repertoire.

While the absolute number of NK cells and the IFN-γ production and phagocytosis increases in older individuals, the NK-cell cytotoxicity on a ‘per-cell’ basis and the response to IL-2 is impaired. Age-associated increases in NK cells and in T cells expressing NK receptors was suggested to contribute and benefit immunosenescence that might blunt the growth of neoplastic cells in older individuals [21, 80, 305, 312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328].

6.5 T Cell Immunity in Aging

T cell dysfunction is associated with reduced thymic generation of naïve T cells, virus -induced expansion of terminal effectors and increased levels of memory cells producing skewed pro-and anti-apoptotic responses. One of the most critical components of the immune system during aging process is alterations in T cell immunity . The mechanisms that alter the normal homeostatic balance of T cell subpopulations during the aging process and stimulation of pro-inflammatory cytokine production and perpetuating large oligoclonal populations of immune dysfunctional cells are the topics of intense investigations [21, 22, 132, 133, 188, 232, 238,239,240,241, 243,244,245,246, 329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345]. The diminished diversity of the T cell receptor repertoire in aging, in all likelihood, is primarily due to two interdependent conditions:

  1. (a)

    Elevation of pro-inflammatory cytokine milieu present in the elderly;

  2. (b)

    Persistent oxidative stress-induced additional changes in the ratios of immune cells in the direction of Th2 and Treg expression;

A crucial event during an innate immune response is the process of antigen recognition and presentation by antigen presenting cells (APCs ), to specific immune T cells for destruction. Both DCs and macrophages have been demonstrated to possess diverse functions depending on their microenvironments. Age-induced declines in T cell repertoire and accumulation of memory effector cells and genesis of oligoclonal complexes (megaclones) cause a condition of ‘antigen-load ’ that could changes the dynamics of effective immunity in defending the vulnerable tissue against ubiquitous infectious agents or new antigen challenges. Age-associated changes in T cells include shifts in the population of subtypes of naïve and memory T cells which changes the cytokine profiles and T cell proliferative and cytotoxic responses. However, despite the extensive research on characterizing the alterations (decreases) in T cell immunity in elderly, little is known about correlation between immunological changes and clinically relevant decline in health outcomes. It is therefore essential to understand the details of alterations in T cell immunity, the potential relationships with vascular function as well as oxidative-reductive status so that the future of clinical interventions can be designed according to the extent of such changes to better manipulate and restore these fundamental systems for the aging population [30, 31, 309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342].

Overall analyses of data on the role of T cells in the induction of chronic diseases demonstrate that the formation of oligoclonal complexes results from accumulation of combined defects in one or more interdependent immune regulatory events including:

  1. (i)

    Changes in immune response dynamics due to modifications of T cell MHC -binding regions (epitopes);

  2. (ii)

    Alterations in antigen processing components that influence accumulation of terminally differentiated effector T cells;

  3. (iii)

    Increased accumulation of genetic errors, leading to exaggerated or mismatched expression and synthesis of apoptotic and wound healing mediators (creating sustained inflammation);

  4. (iv)

    Skewed expression of Th1/Th2 and Treg in response to infective agents;

  5. (v)

    Skewed lymphocytes clonal expansion or polyclonal complexes and inability of immune and non-immune systems to properly respond to new challenges (e.g., viral, bacterial , neoplastic cells or vaccines);

  6. (vi)

    Release of histamine, a vasoactive component from activated (‘leaky’) MCs , into microenvironment of vulnerable tissue;

  7. (vii)

    Minor or major damages in mitochondrial oxidative phosphorylation and energy status of tissue, contributing to frailty;

  8. (viii)

    Enhanced vulnerability of aging body toward new antigens and infective agents in the induction of chronic illnesses or cancer (Figs. 3.3–3.5).

The changes (decreased) in the ratios of Th1: Th2 responses are likely important contributing factors in age-associated immune dysfunction and multistep carcinogenesis. Release of histamine, an important vasoactive pro-inflammatory mediator (alkaline ) from activated MCs, not only promotes a Th2 response, but it also induces polarization of DCs into Th2 cell-promoting effector DCs or DC2 s via interaction with the Th2 receptor, leading to immune suppression and carcinogenesis. Inhibition of histamine-receptor (H2) to reverse the polarization of activated DCs back to Th1 response and improve immune function in the frail elderly has been postulated [21, 46, 80, 344, 392, 395, 399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422].

The intrinsic process of T cell activation requires interaction between the T cell and antigen presenting cells (APCs ). APCs are responsible for the uptake, processing and presentation of antigen in association with distinct major histocompatibility complexes (MHC) epitopes to antigen receptors on T cells [80, 337, 344, 392, 395, 399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422]. APCs work along with cytokines to initiate and determine the outcome of effector T cell responses.

Given the predominance of the Th2 and Treg response in the elderly, vaccine strategies may need to focus on mechanisms where humoral immunity predominates. In addition, nutritional supplements such as vitamin E, minerals, Cox-2 inhibitors that have shown initial promise for immunomodulation require further systematic investigation to ascertain their role in manipulating the immune system [21, 47, 80, 97,98,99, 327, 331, 337, 345, 399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422].

The T cell population displays an age-dependent decline of the absolute number of total T cells (CD3+), involving both CD4+ and CD8+ subsets, accompanied by an increase of NK cells with well preserved cytotoxic function and by a reduction of B cells . One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T cells (CD95-), which is particularly profound at the level of the CD8+ subpopulation of the oldest old subjects. The progressive exhaustion of this important T cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral neoplastic, bacteria or pathogen-specific vaccines), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells (TH0) that are replaced by large clonal expansion of CD28- T-cells. The origin of CD28- cells has not been completely clarified but it is assumed that they present cells in the phase of replicative senescence characterized by shortening telomeres and reduced proliferative capacity [329,330,331,332,337, 339,340,341,342,343,344,345,346,347,348,349,350].

Upon maturation, T cell polarize into either T helper 1 (Th1) or Th2 cells, based on their cytokine profile.Th1 and Th2 cells represent two polarized forms of T helper cells. T cells which express patterns of both Th1 and Th2 cells are designated Th0 cells and they mediate intermediate effects that depend on the ratio of cytokines produced and the nature of responding cells. Th1 cells are involved in coordination or mediation of inflammatory or immune responses against bacterial , viral, and parasitic infections as well as other allergens or pathogens . The major cytokines associated with Th1 responses are interferon gamma (IFN-γ), tumor necrosis factor-β (TNF-β), interleukin-2 (IL-2) and IL-12. Impairments of Th1 responses have been associated with the pathogenesis of organ-specific autoimmune disorders, such as Crohn’s disease, sarcoidosis, and unexplained recurrent abortions.

Th2 cells produce cytokines such as IL-4, IL-5, IL-6, IL-9 and IL-10. These cytokines are associated with humoral immunity and evoke a strong antibody response in certain diseases such as in accelerated progression from HIV infection, and AIDS , various atopic and inflammatory disorders, parasitic infections and allograft tolerance [21, 285, 329,330,331,332,333,334,335,336,337, 339,340,341,342,343,344,345,346,347,348,349,350].

Better understanding of the roles of Th1 and Th2 cells is of paramount importance for comprehending the mechanisms of protection against infectious agents and the pathogenesis of immunopathologic disorders as well as for the future directions for development of novel therapeutic strategies.

6.6 B Cells and Lymphoid Organ Function in Aging

The lymph nodes (LNs) and spleen have highly organized structural features that would allow interaction between T and B cells and the antigen-presenting dendritic cells (DCs ) on a matrix made up by stromal cells. The optimal structure of the LNs and spleen require formation of tertiary lymphoid organs (TLOs) at the sites of infection or chronic immune stimulation and genesis of germinal centers. The knowledge gaps and controversies on the molecular mechanisms of TLOs formation and functions of these structures under a wide range of inflammatory conditions such as infections , transplantation, autoimmunity, humoral immunity (HI ), as well as, aging processes, make it difficult to better appreciate the important roles that these immune-responsive systems play in health or diseases [21, 24, 30, 31, 336, 344,345,346,347,348,349].

The reported decreases in circulating memory B cells and germinal center formation in the elderly are suggestive of altered function of follicular dendritic-cells that also skew T cell responses and virus -induced expansion of terminal effectors and increased tissue levels of memory cells. The observed loss of response dynamics in innate immune cells and T and B cell subpopulation (cell-mediated immunity-CMI and humoral immunity-HI ) in aging suggests their significant contributions in the increased risk of many infections , autoimmune diseases and other chronic health problems such as cancer in older adults. In addition, the response to vaccination that requires CMI -induced humoral response is significantly decreased in the elderly. Although memory lymphocytes can proliferate fairly rapidly upon stimulation with specific antigens; in general, the generation of such responses in the lung is not necessary unless components of innate immunity are overwhelmed by pathogen challenges that cannot be contained primarily by the innate immune system [21, 329,330,331,332,333,334,335,336, 339, 364].

Oxidative stress-induced skewed clearance ability of immune system and generation of dysfunctional lymphocytes could be viewed as additional foreign elements (self antigens), adding to the ‘pool’ of antigen-load and potentiating inappropriate immune responses and the induction of hyper- or hypo-sensitivity reactions or cross-reactivity, toward a wide range of stimuli that are not normally considered antigenic.

Several elegant studies demonstrate the interactions between thymic epithelial tissues and thymocytes in experimental models of aging [21, 23, 131, 132, 133, 238, 239, 244,245,246, 249, 262, 363, 364]. The analyses of data illuminated many of the fundamental signaling pathways that are involved in regulation of thymopoiesis and the critical control points that potentially could reverse the age-associated thymic involution or immune reconstitution. For example, increased in thymopoiesis was shown in animal models of age-induced thymic involution after marrow transplant, by treatment with IL-7, growth hormone (GH) and Keratinocyte growth factor (KGF). GH therapy was shown to also enhance bone marrow cellularity and multi-lineage hematopoiesis, although improvement in follicular dendritic cells or B cells has not been established [21, 32, 244, 249, 363, 364].

The extension of these studies and applications of growth hormones or other cytokines involved in thymopoiesis and related marrow transplant for human should await a better understanding of the fundamental immunobiological heterogeneities that are unique to humans, particularly when therapeutic approaches are considered for site-specific cancers .

6.7 Germinal Center Dynamics: Antibody -Forming and Memory Cells

During germinal center (GC) reaction, B cells receive signals to produce high–affinity, isotype -switched antibodies as well as differentiate to memory cells or antibody -forming cells (AFCs). Therefore, changes in the GC reaction can dramatically affect humoral immunity . In aged animals, GCs are fewer in number and smaller. Antibodies from aged individuals exhibit less somatic mutation and are of less affinity [21, 41, 137, 356, 363, 364]. In an analysis on heavy genes and lineage trees of post-GC B cells, the mechanisms of somatic hypermutation was found to be intact in aged mice, and the changes in mutations observed in antibodies from aged animals were thought to be due to founder cells effects and/or the process of selection [342,343,344,345,346]. Additionally, striking tissue-specific differences were seen. Many of these observations of diminished germinal center responses can be attributed to poor APC (FDC) and Th cell function. During GC reaction, some B cells are triggered to enter the memory cell pathway. It is clear then, that a poor GC response in the elderly can attribute not only to the inability to clear an existing infection , but also the inability to protect against future infections . Defects in B cell memory are reported at all stages, from generation of memory cells in the GC to poor maintenance of the memory cells due to defective iccosomes, to ineffective reactivation of low-affinity, non-isotype -switched clones [41, 137, 138, 356, 363, 364]. B cell themselves may be defective in generating memory. GC reaction was suggested to be intact in aged mice, but its function merely delayed for B cell antibody production as demonstrated in a number of studies. Using murine model of aging it was shown that aged B cells were able to produce high affinity, isotype -switched antibodies in response to TD antigen, when provided with an appropriate environment. Another plasma cell population, the long-lived bone marrow plasma cells are decreased in number and have fewer germline mutations than AFCs in young animals [138, 356, 363, 364]. These studies suggest that B cell responses in aged animals are not defective but may merely have slower kinetics or decreased specificity.

6.8 Role of Neutrophils in Remodeling Extracellular Matrix and Angiogenesis

Polymorphonuclear cells (PMNs) are not a major constituent of the leukocyte infiltrate, they might have a key role in triggering and sustaining the inflammatory cascade. Analyses of several reported data suggest that neutrophils participate in acute inflammatory processes, particularly during termination of inflammation (Yang or wound healing ) and/or induction of tumorigenesis [21, 31, 365, 366, 367, 369, 393]. Briefly, during termination of an acute inflammation (Yang), neutrophils respond to signals of IL-8, expressed from activated innate immune cells, and release a series of enzymes that are involved in remodeling of the extracellular matrix (ECM) and neovascularization of target tissue. Activated neutrophils initially adhere to vascular endothelium and then potent binding occurs during this reaction. Adhesion molecules expressed on granulocytes such as CD11a, CD11b, CD18 are involved in these phenomena. After the initial reactions, granulocytes migrate out of blood vessels via LFA-1 (CD11a.CD18) and Mac-1 (CD11b/CD18) to exert bactericidal effects [21, 31, 365,366,367, 369, 393, 492,493,494,495,496,497]. Neutrophils-induced ECM remodeling involve activation of enzymes, such as matrix metalloproteinases (MMPs) including MMP-9 (gelatinase B), a family of Zn2+-dependent extracellular proteases, to initially digest extracellular components (acting initially in the apoptotic arm of Yin process?). Following their actions, these enzymes are inhibited or inactivated by the tissue inhibitors of metalloproteinases (TIMPs). Neutrophils activation by IL-8 signaling and ECM remodeling processes also involve release of specific sulfatase and heparanase and growth factors (e.g., bFGF, chemoattractants) expressed from activated vascular endothelial cells and lymphocytes. The ECM remodeling events would allow activation and migration of neutrophils and expedites the recruitment of other immune cells responding the inflammatory cascade established by IL-8 release. It is suggested that the action of enzymes and growth factors that are involved in remodeling of the extracellular matrix provide less resistance or temporary loss of matrix integrity during termination of inflammation. Under oxidative stress or during carcinogenesis, lack of ECM resistance could provide an opportunity to facilitate influx of clumps of tumor cells and take advantage of the diminished cell-cell interactions in favor of tumor infiltrations and subsequent metastasis in secondary organ systems. Therefore, the presence of growth or wound healing factors could facilitate tumor angiogenesis and create an environment to further use wound healing signals such as IL-8 to attract neutrophils for remodeling in favor of tumor angiogenesis . Indirect support for the suggestion comes from analyses of related data that show another cytokine such as M-CSF induces cytokine production by monocytes (e.g., MΦs ) and secondarily enhances expression of cell adhesion molecule (CAM) and superoxide anion production by granulocytes. In this process, IL-8 was reported to accelerate granulocyte chemotaxis and expression of adhesion molecules such as Mac-1 (CD11b/CD18), as well as synthesis of superoxide anion production by granulocytes [21,22,23, 31, 32, 80, 171, 276, 368, 497]. Teranishi et al. [368] showed that IL-8 production by monocytes from ovarian cancer patients, at day 14 after chemotherapy , dose-dependently increased with M-CSF, while the levels of GM-CSF and G-CSF secretion were not influenced. In general, the biological systems involved in IL-8 production by monocytes seem to have important roles in activation and expression of other cytokines such as the M-CSF and potential improvement of granulocyte functions. They also could secondarily enhance neutrophils chemotaxis that are further influenced by IL-8 expression of monocytes.

6.9 Mast Cells: Innate Immune Cells Possessing Effector Cell Properties

In mammalians, including humans, mast cells (MCs) as other immune cells originate from the hematopoietic lineage. MCs complete their differentiation in various peripheral tissues, and ubiquitously present in organs throughout the body. Originating from CD34+ progenitor cells in the bone marrow, mast cells circulate as undifferentiated mononuclear cells in the peripheral circulation and express c-kit (CD117), the receptor for stem cell factor [21,22,23,24,25,26, 30, 50, 51, 80, 367, 373,374,375,376,377,378,379,380,381,382]. MCs have tendency to localize around blood vessels, nerves, glandular duct as well as inflammatory neoplastic foci (Figs. 3.4 and 3.5). All MCs possess common characteristics of cytoplasmic granules storing biogenic amines (e.g., vasoactive histamine) and acidic proteoglycans (e.g., heparin), expression of plasma membrane receptors binding for IgE antibodies , cytokines and neutral proteases. However, MC populations are heterogeneous and show marked differences in their phenotypic expression of different proteases in their granules in distinct anatomical sites. Mast cell containing tryptase (MCT), also known as immune cell associated MCs, are predominantly located in the respiratory and intestinal mucosa, where they co-localize around T lymphocytes. MCs containing both tryptase and chymase (MCTC) are predominantly found in connective tissue areas of the skin, conjunctiva and synovium. MCs stain metachromatically, because of the presence of sulphated glycosaminoglycan heparin. In many organs and under physiological conditions, MCs are numerous close to the capillaries. Maintenance of MCs growth is facilitated by dermal endothelial cells expressing growth mediators and chemotactic stem cell factor (SCF) [21,22,23,24,25,26, 30, 50, 51, 80, 367, 373,374,375,376,377,378,379,380,381,382, 386, 397,398,399,400,402,403, 405,406,407,408,409,410,411,412,413,414,415,416,417,418].

Possessing and expressing a wide range of biologically active mediators within their granules and cellular membranes, mast cells are considered multipotent effector cells of the immune system. Mast cells express a number of functionally important cell surface antigens and growth factors , such as stem cell factor receptor (SCFR also called kit ligand or CD117) as well as immunoglobulin E receptor (IgER, FC high affinity epsilon receptor). Tryptases (alpha and beta) are selectively and abundantly produced by mast cell degranulation and the levels of tryptase in the circulation provide a precise indicator of mast cell activation [e.g., during anaphylaxis ]. Systemic anaphylaxis arises when mast cells, possibly along with other cell types, are provoked to secrete mediators that evoke a systemic response including vascular hyperpermeability reactions. Generally, in anaphylaxis elevations of histamine levels in circulation have been detected. However, suggestions of involvement of other innate immune cells such as basophiles and release of additional histamine in genetically modified food allergy-induced conditions such as asthma , utricaria, angioderma, atopic dermatitis, conjunctivitis, shock and cardiac arrhythmias deserve further studied (see Chaps. 5 and 6) [21].

Upon activation, MCs can induce or promote degranulation , migration, and/or cytokine production through respective ligand binding. Interactions and communication of external and internal molecules of activated mast cells can mediate surface molecule adhesion and also cell aggregation. The extent of mast cell activation and physiological responses e.g., expression of critical molecules on the surface of mast cells, depends not only on the extent of signal on the effected tissue/organ environment, but also on the stage of cell maturation. Under a variety of conditions mast cells express variable amount of activated surface antigen proteins such as CD25, CD63, CD69, CD88; cell recognition molecules, such as CD2, CD11, CD18, CD 50, CD54 or cytokine receptors [21, 80, 367, 373,374,375,376,377,378,379,380,381,382, 386, 397,398,399,400,402,403, 405,406,407,408,409,410,411,412,413,414,415,416,417,418].

MCs are recognized as the key cells in immediate or type 1 hypersensitivity reactions. However, their distribution throughout serosal and mucosal tissues and their close proximity to blood vessels have suggested their involvement in several other diseases. The number of MCs, primarily non-functional MCs, rise in pathological conditions often during oxidative stress involving increased angiogenic activity, such as psoriasis, atherosclerosis, rheumatoid arthritis, haemangioma and other neoplasms and tumorigenesis [21, 80, 367, 373,374,375,376,377,378,379,380,381,382, 386, 397,398,399,400,402,403]. We suggested that the rise in number of MCs, was due to oxidative-stress-induced production of unscheduled (not fully granulated) or increased in number of ‘leaky’ mast cells [21,22,23,24,25,26, 50, 80]. The extent of mast cell granulation and degranulations, or “leakiness” could determine the tumoricidal vs tumorigenesis function of MCs and contributions in cell growth. It was further hypothesized that the release of low-level histamine (independent from antigen-specific IgE -fc binding receptor aggregation), from ‘leaky’ or exhausted MCs in the microenvironment of tissue could signal for induction of angiogenesis and tumorigenesis (Fig. 3.5). Similar to allergic rhinitis, the atopic dermatitis, asthma , or conjunctivitis are often accompanied by increased circulating IgE. However, the circulating levels of IgE may not always correlate with the extent of clinical reactions as we reported for conjunctival-associated lymphoid tissues (details in Chaps. 4 and 6) [21, 23, 50]. In acute (immediate) inflammatory responses or hypersensitivity (type1) reactions, activation of MCs leads to crosslinking of receptor molecules Fcε RI-IgE and release of preformed vasoactive mediators such as histamine, synthesis of prostaglandins and leukotrienes, and the transcription of several other inflammatory cytokines, oxidants and neurotransmitters (Fig. 3.4) [21, 80, 367, 373,374,375,376,377,378,379,380,381,382, 386, 397,398,399,400,402,403]. The inflammatory mediators rapidly induce mucosal edema and mucus secretion, constriction of smooth muscle and hyperpermeability of vasculature to facilitate inflammatory cell infiltration.

Fig. 3.5
figure 5

Schematic representation of mast cells activities in acute and chronic inflammation and the induction of angiogenesis and tumorigenesis tumorigenesis. Modified from Khatami [30] Exp.Opin. Biol. Ther. 2008. All rights reserved. See text.

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Histamine, a potent vasoactive mediator of mast cell degranulation , exerts its effects via at least three receptors, H1, H2 and H3 expressed on vascular endothelial and lymphoid cells and the neuronal systems including the brain [21, 22, 50, 51, 80, 386, 397,398,399,400,402,403]. Histamine is a regulator of inflammatory responses and promotes allergic reactions, gastric acid secretion, and tumorigenesis . Studies using antibody titers and delayed type hypersensitivity reactions in rats demonstrated H2 selective antihistamines improved responses in HI and CMI . Analyses of data on using histamine H2 antagonists demonstrated boost of the proliferative response of T cells to IL-2 and improved healing of Herpes Zoster as well as increased survival of patients with gastric and colorectal cancers. The overall analyses of data on these and related studies on inhibition of histamine receptors seem to support the author’s hypothesis that using mast cell stabilizers may be immunologically effective in preventing multistep pathways of tumorigenesis in mast-cell dependent tissue growth stimulation (details in Chap. 6 ) [21, 50, 80]. Among several mediators affected by continuous release of histamine into the target tissue are inhibition of apoptotic cytokines (e.g., IL-12, involved in Th1 responses or Yin), stimulation of IL-10 (mediated by H2 receptor during Th2 response and immunosuppressive or Yang) [21, 22, 50, 51, 80, 284, 285, 306, 307, 340, 360, 386, 397,398,399,400,402,403]. It was suggested that continuous release of histamine signals for shifts (decrease) in the dynamics of adaptive immune cells (Th1/Th2 ratios), similar to, or contributing to the response shifts occurring in favor of Th2 response immune compromise , and the observed increased allergic reactions in frail elderly (details in Chap. 6 ) [21, 80]. The hypothesis is further supported by an increased severity of inflammatory responses and inappropriate feedback control loop observed in atopic disorders and increased asthma in aging. The evidence also supports the use of H2 antihistamines to restore the Th2/Th1 and/or downregulate Th2 responses seen in the elderly. If the Th2 response could be restored to a level that is seen in the healthy individuals, a more normal Th1/Th2 ratio would result in improvement of immune function.

Through H1 and H2 receptor molecules , histamine also polarizes human immature DCs (DC1) into Th2 cell-promoting effector DCs (DC2 or TADCs) that would contribute to the immune suppression [21,22,23,24,25,26,27, 80, 308, 419, 420, 424]. As previously suggested, in acute inflammation , histamine initially signals for Th2 polarization and expression of growth factors for termination of inflammation. However, prolonged release of histamine (independent of IgE -binding to receptor occurs by ‘leaky’ MCs ) is likely an attempt to induce termination of inflammation by induction of Th2 polarization (Yang). Overexpression of the CSF-1 and/or its receptor c-fms in mammary glands of transgenic mice results in hyperplasia and tumor formation [226]. Binding of CSF-1 to its receptor c-fms, which is a cell surface receptor belonging to a family of tyrosine kinase receptors, results in the dimerization and phosphorylation of c-fms, leading to macrophage proliferation via signal transduction pathways. Studies involving certain hematopoietic growth factors , such as CSF-1, have demonstrated that these substrates also affect normal and malignant cells of nonhematopoietic origin. Involvement of MCs and/or high expression of CSF-1 has been associated with a variety of disorders such as stroke, conjunctivitis, gynecological cancers (ovarian adenocarcinoma), non-Hodgkin lymphoma and hyperplasia, neoplasia and other cancers [21, 22, 23, 80, 226, 384, 389].

It is suggested that the release of low-level histamine, a negatively charged vasoactive agent, produced non-specifically in the microenvironment of tumor associated MCs (TAMC) or ‘leaky’ MCs is an immune suppressor, similar to production of arginine (also a negatively charged/alkaline amino acid) release from activated MΦs (TAMs or M2 phenotype) in the direction of tumor growth promotion (Figs. 3.4. and 3.5) [21, 22, 23, 80].

Mast cells have been shown to directly and indirectly influence growth and cellular functions of eosinophils , macrophages and T cells. The mediators involved, include T cell-derived IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF ). These mediators also play a role in eosinophil activation, chemotaxis, and macrophage growth promoting activity. Mast cells also induce the release of factors/cytokines for program cell death, tumor necrosis factor-α (TNF-α) that interacts with eosinphil chemotaxic during apoptosis and cell growth arrest . Furthermore, synthesis and release of factors, such as mast cell/stem cell factor (SCF)-c-kit and its receptors regulates the function of mast cells. The level and nature of cytokines and chemokines present in the tissue would perhaps produce signals that regulate the activation or suppression of oncogene pathways such as Ras-MAPK through c-fos gene expression and induction of cancers or other systemic diseases (Figs. 3.4 and 3.5) [21,22,23,24,25,26, 50, 80, 375,376,377,378,379,380,381,382].

6.10 Function of Dendritic Cells in Immunity and Aging

Dendritic cells (DCs), originate in the bone marrow and found in peripheral sites of antigen uptake (skin, spleen, thymus, colon and synovia) as well as the blood. They are routinely responsible for initiation, activation and outcome of effector T cells (Th1 or Th2) resulting in immune responses. Resting immature DCs , also called DC0s, are derived from monocytes and are highly efficient for capturing foreign antigens. DCs form a network of sentinel cells in the periphery to capture and transport/ferry pathogenic antigens to secondary lymphoid tissues. Therefore, DCs are crucial for the initiation of primary immune responses [21, 52, 80, 308, 335, 419,420,421,422, 424,425,426,427,428,429,430,431, 439].

At least two classes of dendritic cells are considered as highly specialized APCs . However, other phenotypes of DCs have been identified in site-specific tissues under a wide range of inflammatory conditions and experimental model studies. The following outlines the origins and basic function of dendritic cells in immunity:

  1. (a)

    Class 1 DCs – induction of tolerance. Derived from bone marrow, DCs present the processed antigen to T cells and act as ferry for delivery/presentation of processed antigens to the naïve and memory T cells resulting in CD4+ and CD8+ immunity and tolerance. These cells do not synthesize antibodies or many cytokines and are not normally involved in phagocytic or antimicrobial activities.

  2. (b)

    Class 2 DCs -follicular dendritic cells (FDCs): FDCs are involved in presentation of native antigens as immune complexes to B cells to develop antibody memory-affinity maturation and immunity. The origins of FDCs are not clear but they may also arise from bone marrow.

Immature DCs (DC0 s, resting cells) are thought to undergo step maturation or transition (polarization ) from type 1 (tumoricidal ) dendritic cells (DC1) and type 2 (tumorigenic ) dendritic cell phenotypes (DC2) during stimuli-induced migration and under the influence of growth factors /cytokines such as IL-1β [419,420,421,422, 424,425,426,427,428,429,430,431, 439, 452]. The inflammatory signals, that are involved in DCs maturation and migration to lymphoid organs, also induce a chemokine receptor switch, which normally cause down-regulation of inflammatory receptors (such as CCR1, CCR2, CCR5) and induction of CCR7, perhaps as contributing signals for termination of an acute inflammation (Yin-Yang ). For example, concomitant tissue exposure to lipopolysaccharide (LPS , stimuli) and IL-10, blocks the chemokine receptor switch associated with DC maturation. LPS + IL-10-treated DCs showed low expression of CCR7 (signal for apoptosis Yin arm?) and high expression of CCR1, CCR2 and CCR5. These chemokines receptors were unable to elicit migration. Relevant data showed that uncoupled receptors expressed on mixture of LPS + IL-10-treated cells sequester and scavenge inflammatory chemokines . Similar results were obtained for monocytes exposed to activating signals and IL-10. Thus, in an inflammatory environment, it is likely that IL-10 generates functional decoy receptors on DC and monocytes, which act as molecular sinks and scavengers for inflammatory chemokines , to regulate and terminate (resolve) inflammation [21,22,23,24,25,26,27, 419,420,421,422, 424,425,426,427,428,429,430,431, 439, 452].

Since small numbers of DC are sufficient to induce an immune response, DCs are the most potent stimulator cells of T cells. Analyses of related data suggest that in addition to their roles for presentation of processed antigen to T cells during the induction of tolerance, DCs seem to be the only APCs capable of presenting novel antigens, to resting naïve T cells to initiate the primary immune response. This important feature of DCs has currently become the focus of considering DCs as prime targets for immunotherapy. Therefore, due to the highly importance of the DCs, any minor modulation in DCs function could result in significant alterations in immune responses. As recent data suggested, methods could be developed in the near future to provide elderly individuals with protection through enhanced route of administration, such as repeated vaccination (details in Chaps. 5 and 6) [422, 424,425,426,427,428,429,430,431, 439, 452].

Major or minor alterations in the number or function of DCs are associated with immune dysfunction , in chronic/persistent inflammation and the aging process [21,22,23,24,25,26,27, 80, 422, 424,425,426,427,428,429,430,431, 439, 452]. These changes include:

  1. (a)

    Oxidative stress-induced DCs polarization to DC2 phenotypes (perhaps on both classes of DCs ) and maturation processes resulting in the loss of capacity to capture antigen, increased capacity to present processed antigens to T cell due to increased expression of surface molecule involved in chemotaxis and T cell activation of major histocompatibility complexes I and II and costimulatory molecules (e.g., (CD-40) or potential loss of tolerance to antigens that ordinarily do not stimulate responses from T cells.

  2. (b)

    Mature DC2 also produce T cell stimulatory cytokines IL-12 and IFN-γ. Soon after antigen specific interaction with T cells, mature DC undergo apoptosis via CD40 and FAS ligation, a mechanism thought to regulate unnecessary and excessive T cell or perhaps natural killer cells activation and expansion.

While, the current approaches to modulate the activities of DCs for, immunotherapeutic vaccination methods against infectious diseases in frail older adults are attractive, applications of such strategies require detailed understanding of the potential interactions and synergies between DCs and other APCs in site-specific tissues for effectiveness of such approaches as we recently demonstrated in conjunctival-associated lymphoid tissues [22, 80] (details in Chaps. 4 and 6).

6.11 Role of Macrophages in Acute and Chronic Inflammation and Aging

Macrophages are terminally differentiated cells of bone marrow derived from peripheral monocytes and reside in tissues (Fig. 3.3). In general, activation of monocytes by pathogens /microbial or their fragments, cause expression of pro-inflammatory death signals and mediators leading to migration into tissues and differentiation to pro-inflammatory cells or MI (tumoricidal ), which are involved in the destruction of microorganisms and neoplastic cells. M1 function includes activation of other innate and adaptive immune cells and non-immune (vasculature , metabolism and neuronal ) responses that facilitate enhanced synthesis and release of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-12, and IL-23 and expression of chemokines such as CCL5, CCL8, CXCL2, and CXCL4 (Figs. 3.3 and 3.6) [21,22,23,24,25,26, 80, 260, 308, 337, 367, 368, 384, 393, 435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451, 504].

Fig. 3.6
figure 6

Schematic representation of pleiotropic properties (duality ) of macrophages (MΦs) in acute and chronic inflammation. Self-termination acute inflammation induces generation of a wide range of precise signals for apoptotic and wound healing from activated MΦs in their M1 and M2 (tumoricidal vs tumorigenic ) phenotypes (A, left panel, Yin = Yang). The mediators include tumor necrosis factor alpha (TNFα), interleukins (ILs, IL-1, IL-12), interferon gamma (INF-γ), chemokines (e.g., IP-10 or CXCL10 or MIG- CXCL9), inducible nitric oxide synthase (iNOS) for arginine (Arg) metabolism , matrix metalloproteases (e.g., MMP-2, 7, 8, 9), reactive oxygen species (ROSs), reactive nitrogen species (RNs) other chemokines (e.g., CXCL 1) as well as expression of NF-kB and wound healing pathways. The outcomes are destruction (lysis) of viruses , defective tumor cells and infected host tissue as well as termination of inflammation and tissue repair. The B (right panel) oxidative stress-induced hypoxia favors polarization of MΦs in M2 (TAMs) phenotypes and expression of tumorigenic factors including activation of arginase and ornithine pathways toward polyamine biosynthesis, generation of decoy receptors in IL-1 RA (IL-1dR), MMPs (MMP-2, 9, 10, 11) or ILs (IL-3, IL-4, IL-10, IL-13), chemonkines such as CCL24 (Eotaxin-2), CCL18, CXC, MDC/CCL22, Cytp1B, which influence tumor growth, neoplasia, angiogenesis , and metastasis. Alterations in the ratios of M1/M2 impact cell-mediated immunity (CMI ), Th1/Th2 ratios including regulatory T cells (Tr/ CCL22) leading to immune suppression and tumorigenesis (Modified from Ref. [23] with permission, All right reserved)

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Macrophages occupy distinct regions of lymphoid tissues in the gut and mucosa. MΦs are influenced and activated by signals from intracellular microbial cell walls and by cytokines (e.g., TNF or IFN-γ), to produce numerous cytokines, enzymes, reactive oxygen species/ROS , reactive nitrogen species/RNS to kill intracellular microbes and to clear antigens, from the B cells and/or follicules of the lymphoid organs, the mucosal surface of the gut and the circulation . In addition, B cell proliferation and induction of plasma cell for specific antibody production are influenced by signals from surface Ig receptor proteins from immune cells or lymphocyte-derived cytokines (lymphokines) such as IL-2, IL-4, IL-5, under inflammatory conditions, and could influence the dynamics of immune responses [balance between tumoricidal (Yin) and tumorigenic (Yang) properties] in the direction of tissue necrosis or growth and induction of chronic diseases (Figs. 3.5 and 3.6).

Macrophages have major roles in tissue remodeling and repair in inflammatory conditions and ontogenesis in adult life. Macrophage heterogeneity , possessing at least two types of cells (M1 and M2) perhaps reflects the plasticity and versatility of these cells in response to exposure to diverse microenvironmental signals. The immunoregulatory roles of these cells are increasing being recognized [21,22,23, 80, 260, 308, 337, 367, 368, 435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451, 504]. Differential cytokine production (pro- and anti-inflammatory mediators ) is a key feature of polarized macrophages. The classically activated M1 macrophages are potent effector cells that kill microorganisms and lyse the tumor cells by producing copious amount of proinflammatory cytokines. In contrast, TAMs or M2 phenotypes produce a host of growth factors that affect tumor-cell proliferation, angiogenesis and the deposition and dissociation of connective tissues. By expressing cytokines from M2 (TAMs) phenotypes, MΦs participate in circuits that regulate tumor growth and progression, adaptive/acquired immune dysregulation, stroma formation and angiogenesis . Inflammatory conditions, causing dynamic shifts in immune responses include alterations in the ratios of polarized APCs , infiltrating macrophages, changes in the T cell subpopulation (e.g., decreases in Th1:Th2) that could promote tumor progression and metastasis in a cascade of events (Fig. 3.6).

The progressive immune dysfunction raises the possibility that systematic monitoring of molecular and cellular profiles involved at identifiable phases of inflammation-induced tumorigenesis might represent novel and valuable therapeutic targets. For instance, arginine metabolism is characterized by high levels of inducible nitric oxide synthase (iNOS) in M1 cells, whereas the arginase pathways predominates in the M2 cells with generation of ornithine and polyamines (Fig. 3.6) [21,22,23,24,25,26, 80, 367, 368, 384, 393, 435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451, 504]. Others have shown that inhibition of polyamine synthesis has been used in preclinical studies for cancer chemoprevention. Whether inhibition of polyamine synthesis restores antitumor properties of macrophages , e.g., shifting the ratios of M1: M2 polarities and favoring their tumoricidal effects, are yet to be understood. CCL8, for example, is a highly inducible chemokine that is clearly responsible for the elicitation of neutrophils as part of an innate response to a wide variety of challenges. In contrast, CCL19 and CCL20 chemokines are expressed constitutively and are intimately involved in the basal migration patterns of T cell and the formation of secondary lymphoid organs involved in adaptive response [21, 435,436,437,438,439,440].

As schematically demonstrated in Fig. 3.6, the maintenance of body homeostasis requires maintaining a proper ratio of both M1 (tumoricidal ):M2 (tumorigenic or TAM) phenotype of macrophages . This balance is disturbed during altered immune response dynamics and unresolved inflammation in aging. Tumor associated macrophages (TAM) and the M2 phenotypes demonstrated similar functions in immune suppression and promotion of cell growth. M2 and TAMs phenotypes are poor APCs and express little apoptotic factors (IL-12) or toxins such as NO , but express high levels of mannose receptors (MR) and IL-10 primarily involved in growth promotion. Therefore, polarization of macrophage (and other innate immune cells) is a simplified model for conceptual framework of feedback control mechanisms describing how the Yin and Yang of acute inflammation may continue diverse operation of immune responses in health and diseases [21,22,23, 80, 260, 368, 384, 393, 435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451, 504].

In brief, the sequence of events and diverse biological activities of macrophages (professional APCs ), under a wide range of acute (simultaneous Yin-Yang events) or chronic inflammatory conditions that may lead to tumorigenesis includes, but not limited to, the following (Fig. 3.6):

  1. (a)

    Polarization /activation (M1) for recognition of antigen, induction of TLR molecules;

  2. (b)

    Cytotoxicity and phagocytosis, burst of energy (ATP ) from mitochondrial oxidative phosphorylation for antigen processing involving secretion of biologically active molecules, generation of toxins and oxidants (e.g., TNF-a, IL-1, caspases, NO ) and related receptor molecules ;

  3. (c)

    Activation of cytotoxic T lymphocytes, NK cells and vasculature and generation of signaling molecules and receptors (e.g., MHC class I or II , CAMs , platelets activation) to facilitate apoptosis ;

  4. (d)

    High capacity for presentation of antigen to antigen-naive T lymphocytes;

  5. (e)

    Activation, migration and differentiation of monocytes such as DCs in the direction of pro-inflammatory process for additional required oxidants and toxins for destruction of pathogens and target tissue;

  6. (f)

    Immune response towards Th1 and/or Th17;

  7. (g)

    Control/regulation of inflammatory process through induction of M2 (tumorigenic or TAM) phenotype during termination phase of acute inflammation (Yang);

  8. (h)

    Termination of inflammation occurs by induction of decoy receptor molecules (e.g., IL-1 dR, TNFdR or IRAK-M ), activation of arginase, induction of suppression of adaptive immune cells through expression of factors [e.g., NFkB , PGE2 , IL-10, CCR2/CCL2, CCL17 and CCL22, MMP-2 and MMP-9, urokinase-type plasminogen activator (uPA)]. Expression of these wound healing mediators of M2 also facilitate tumor invasion and influence induction of Th2 phenotype, influx of T regulatory cells (Treg) and altered TCR during tumor growth promotion;

  9. (i)

    Activation of B and plasma cells and induction of higher expression of certain membrane/surface receptors, including type 2 Fc receptor for IgG (Fc-R2, CD23), mannose receptor (MR), and receptor for LPS (CD14);

  10. (j)

    Suppression of adaptive immunity, remodeling and repair of damaged target tissue and termination of inflammation;

  11. (k)

    Persistent oxidative stress or aging could induce infiltrations, interactions and synergies of TAMs to the site of injury by activated host immune cells in the direction of immune suppression and tumorigenesis ;

  12. (l)

    Induction of hypoxia and expression of mismatched apoptotic and growth factors (immune chaos or immune tsunami ) facilitate enhanced growth requirements of cancer cells with oncogenic features could lead to immune suppression and opportunities for tumor cells to evade immune surveillance ;

Furthermore, maintenance of macrophages in TAM phenotype is assisted by T cells infiltrating human tumors in Th2 phenotype, with a predominance of CD8+ in conditions such as Kaposi’s sarcoma, perhaps gastric malignancies or colorectal cancer. Presence of TAM further induce expression of growth promoting mediators such as IL-4, IL-13, IL-10 or PGE2 , which facilitate skewing of macrophage polarization in tumor environment. However, infiltration of TAM at site-specific tumors may not correlate with cancer patients’ survival, as the presence of M1 in tissue have been shown to have cytotoxic and apoptotic activities that compensate for growth promoting activities of TAM in improving survival. As recently suggested, promotion of Yin and Yang activities of immune cells such as enhancing anti-tumoricidal properties of M1 in certain regions of neoplastic tissue may improve survival [21,22,23,24,25,26,27, 30, 50, 80]. As noted above, TAM are capable of modifying subunit of T cell receptor (TCR -ζ) or T-helper lymphocytes, which play a role in the activation of Th2 leading to induction of energy and apoptosis of T lymphocyte (Th1). Therefore, as with other immune cells, the duality or immunoregulatory roles of macrophages contribute to the fate of tissue repair, growth promotion or necrosis under a wide range of inflammatory conditions [21,22,23,24,25,26,27, 30, 50, 80, 431, 303, 337, 434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451].

As schematically represented in Fig. 3.6, chemokines expressed from MΦs present both growth-arresting (Yin) and growth-promoting activities in vitro and in vivo depending on the conditions that they exert their effects. In general, in acute inflammation inducible chemokines are involved in attracting leukocytes (e.g., DCs , MΦs ) to the tissue site of inflammation while constitutive chemokines control the basal trafficking of T lymphocytes for termination/resolution of acute inflammation . For example, monocyte chemoattractant protein-1 (MCP-1) , also known as macrophage chemoattractant protein (CCL2), fits the role of inducible chemokine . At basal (resting), MCP-1 is rarely expressed but under inflammatory conditions, it can be rapidly induced [21,22,23,24,25,26,27, 30, 80].

Oxidative stress-induced expression of chemokines (e.g., CCL2, CCL22, CCL18) from activated MΦs (M2/TAMs phenotypes) are involved in amplification and regulation of the polarized immune cells such as T cell responses and often lead to changes in the Th1 to Th2 ratios influencing immune suppression and tissue growth in the direction of tumorigenesis or cancer. Reports on the formation of fibrous tissue in tumor stoma are major features in human tumors. Fibrous tissue formation, known to encapsulate parasites (or perhaps their substructures) could induce oxidative stress and continuous activation of M2 (TAMs) that signal for expression of chemokines or growth factors (e.g., CCL2 and IL-13, or TGF-β ) and the induction of Th2 responses and suppression of apoptosis . It should be noted that nearly all tumor cells produce and/or induce abundant quantities of several chemokines (e.g., CCL2, M-CSF , TGF-β ), in the direction of growth survival by either changing the receptor function (expression of decoy receptors ) or by altering the chemokine response function that result in “hijacking” and satisfying their enhanced growth requirements (Fig. 3.6) [21,22,23,24,25,26,27, 30, 50, 80, 303, 337, 434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451].

6.12 Inefficiency of Immune System to Overcome New Challenges in Aging. A Cycle of Skewed Response Dynamics in Immune and Non-immune Systems

Immunosenescence is the result of minor and major skewed responses of immunity, including altered functions of vasculature and metabolic response dynamics that affects the immune-responsive and immune-privileged tissues as the bases for the genesis and progression of a wide range of age-associated chronic diseases . Numerous reports clearly indicate that the activity, availability and function of immune, vascular, hormonal and neuroendocrine systems change or deteriorate with aging. For instance, as the organisms age, changes in the activities, architectural and function of immune and non-immune systems influence reproductive, morphological, behavioral and biochemical properties in the organs/tissues. Age-related increased oxidative damage in a variety of cell types (e.g., T and B cell , APCs , mucus-secreting goblet cells , epithelial or endothelial cells) or cellular components (mitochondria, ER, lysosome, Golgi apparatus ) and molecules (e.g., DNA/RNA, proteins and lipids) or transport systems in organisms, invertebrates or humans have been demonstrated [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45, 80, 196, 197, 300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369]. Analyses of relevant data suggest that immunosenescence is not accompanied by progressive deterioration of the immune function, but it is rather the result of immune system remodeling where some functions are reduced, others remain unchanged or even increased. It appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison with the more acquired sophisticated adaptive compartment that exhibit profound modifications. Furthermore, data on biology of aging strongly suggests that continuous (chronic) up-regulation of pro-inflammatory mediators (e.g., TNF-α, IL1-b, COX-2, iNOS) that are expressed in aging are due to redox imbalance that activates many pro-inflammatory signaling pathways, including NF-kB signaling pathway [21,22,23,24,25,26,27,28,29,30,31, 186, 303, 335, 337, 380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497,498,499,500,501,502,503,504,505,506,507,508,509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530,531,532,533,534,535,536,537,538,539,540,541,542,543,544,545,546,547,548,549,550,551,552,553,554,555,556,557,558,559,560,561,562].

7 Cytobiology of Vasculature , Platelets and Complement in Acute or Chronic Inflammatory Diseases

Vasculogenesis is the earliest event in the fetal growth development. Activation of vasculature , neovascularization and angiogenesis are also normal required physiological events for growth and development, and facilitation of acute inflammatory conditions.

At resting, the homeostasis of vascular function (toning) and integrity is maintained by basal expression of vascular-derived angiognenic and anti-angiogenic factors. Mediators of activated vascular components participate in both apoptosis and wound healing processes. During inflammation, activation of vascular tissue components is necessary for increased vascular permeability (hyperpermeability) and infiltration of inflammatory cells to the target tissue. Stimuli induces vascular tissues to express mediators such as cell adhesion molecules (CAMs) , vascular endothelial growth factor (VEGF ), endostatin, epidermal growth factor (EGF ), heparin and histamine receptors, membrane metaloproteases-MMPs. Other events such as activation of histaminase, heparinase or inhibitors of prostaglandin synthesis or NOS also participate during vascular tissue activation and inflammatory processes. These events are required for regulation of vascular permeability and passage of blood components (e.g., inflammatory cells, plasma proteins or complements), differentiation and migration of cells at the site of injury during both apoptosis and wound healing processes and for termination of inflammation (Figs. 3.5 and 3.6) [21,22,23,24,25,26,27, 30, 50, 80, 338, 452,453,454, 456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477].

Considered the tree of life, vasculature plays key roles in health and diseases with three principal functions:

  1. (a)

    Delivery of nutrients and oxygen to tissues/organ systems and removal of gases and waste products from the tissues throughout the body;

  2. (b)

    Gate-keeper of immune cells; involved in proliferation, differentiation and infiltration of inflammatory cells into stimulated (infected or injured) targeted tissues, facilitate both apoptosis (Yin) and wound healing (Yang) processes;

  3. (c)

    Maintenance of crosstalk between neuronal -immune systems and organs/tissues;

Being the gatekeepers for leukocyte trafficking, vasculature was suggested to play a most crucial role during both arms of ‘Yin’ (apoptosis ) and ‘Yang’ (wound healing ) responses with active participation of neuronal pathways and induction of mediators such as cortisol, epinephrine or norepinephrine [21,22,23,24,25,26,27, 30, 50, 80]. Upon tissue stimulation, vascular responses include leukocyte activation; differentiation and migration to the target/injured tissue; appropriate expression of cytokines and chemokines and receptor molecules as well as vascular-derived neuronal /hormonal components (epinephrine, norepinephrine, cortisol) during tumoricidal (growth-arresting ) and tumorigenic (growth-promoting) responses. In an acute inflammation , activation, infiltration and trafficking of leukocytes to target tissue often involve vascular hyperpermeability reactions and crosstalk between mediators of immune inflammatory cells (e.g., TLR , TNF-α, ILs) and vascular components (e.g., CAMs , VEGF , FGF , PDGF), extracellular matrix and membrane proteases (e.g., ECMs, MMPs), responses from neuroendocine system (e.g., cortisol or epinephrine). A wide range of nutrients, metabolites and gases (e.g., adenosine , glucose, arginine, NO , CO/CO2), hormones (e.g., insulin ), vasoactive components (e.g., histamine) and their respective receptor or surface molecules, also influence blood flow regulation and growth, B and T cell activities that initiate from fetal growth and undergo minor or major changes in aging [21,22,23,24,25,26,27, 30, 37, 47, 48, 58, 87, 117, 452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473]. It should also be noted that under oxidative stress, vascular permeability, function and integrity differentially impact tissues that are immune-privileged or immune-responsive leading to manifestation of site-specific diseases such as neurodegenerative and autoimmune diseases , diabetes and cardiovascular complications or neoplasia and cancer (Figs. 3.5 and 3.6) [21,22,23,24,25,26,27, 30, 50, 80, 224, 338, 399, 408, 452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497].

Outlined examples of major biological properties of angiogenesis in health and chronic diseases and cancer are provided below (Figs. 3.5 and 3.6).

  1. 1.

    Angiogenesis is part of the complex networks of immunity that functions within the highly regulated mechanisms of Yin and Yang of self-terminating properties of effective defense mechanism provided through acute inflammation .

  2. 2.

    Under acute inflammatory conditions, vasculature expresses required angiogenic and anti-angiogenic factors to facilitate both arms of Yin (pro-inflammatory ) and Yang (anti-inflammatory) responses for maintaining body’s protection against harmful foreign elements.

  3. 3.

    Maintenance of vascular quiescence (integrity) normally is achieved by the homeostasis of endogenous inhibitors of angiogenesis (anti-angiogenic) that are balanced by the pro-angiogenic factors.

  4. 4.

    Aging and oxidative stress alter, to varying degrees, the vascular toning or integrity leading to expression or co-expression of anti-, and pro-angiogenic factors and induction of molecular deposition of complexes and micro coagulation (unresolved inflammation) products such as oxidized lipids, proteins, metabolites (e.g., glucose, uric acid or creatinine), and immune cell complexes of under-, or over-expressed mediators that create an antigen-load . The complexes (antigen-load ) could further signal for mismatched responses from immune and metabolic pathways leading to additional aggregated complexes at the vascular bed leading to initiation and progression of organ-specific health problems.

  5. 5.

    Generation of adenosine and receptor molecules (ARs) involves expression of vascular and immune cells ectonucleotidases and surface molecules (e.g., CD39, CD73) that are involved in regulation of blood flow and B and T cell dynamics (e.g., CD4+ and subset of NKT, Treg) during acute or chronic inflammatory conditions. Adenosine involvement in blood flow and immune cell dynamics is particularly important in solid organ transplantation-induced ischemia and promotion of immunogenicity of donor organ that could increase the risk of organ rejection [64, 295, 302, 390, 477, 478,479,480,481, 497, 515].

  6. 6.

    Tumor angiogenesis is associated with a more serious shift in the equilibrium between positive (angiogenic) and negative (anti-angiogenic) regulators of vasculature function that benefit tumor growth.

Several reports present compelling evidence that aging and unresolved inflammation induces minor or major changes in vascular biology and function, involving a wide range of chronic diseases such as adult-onset diabetes complications (e.g., retinopathy , neuropathy, angiopathy, nephropathy), impotence, neurodegenerative and autoimmune diseases , rheumatoid arthritis, stroke, epilepsy, cardiovascular complications, neoplasia/hyperplasia and cancer metastasis. Among the most important reported biological features of vascular dysfunction are neovascularization/angiogenesis , induction of hypoxia , loss of balance between pericytes and endothelial cells association and deposition of molecular complexes [64, 295, 302, 390, 477, 478,479,480,481, 497, 507, 510,511,512,513,514,515,516,517,518,519,520]. Similar to the duality of the immune cells, under physiological conditions, angiogenesis is regulated by maintenance of balance between positive and negative factors and modulators requiring expression of angiogenic and anti-angiogenic factors, involving extracellular matrix proteins, adhesion molecules and receptors, growth factors and proteolytic enzymes. There are distinct gene expression patterns of angiogenic endothelial cells that are characterized by control switches of cell proteolytic balance towards an invasive phenotype as well as by the expression of specific adhesion molecules.

As part of the inflammatory response, the localization of leukocytes depends on cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells (EC). Several reports demonstrate that VCAM-1 expression is induced on human umbilical vein EC (HUVEC) by both TNF-α, and IL-1α), in contrast to human dermal microvascular EC (HDMEC) that only TNF-α leads to expression of VCAM-1. To explosre molecular mechanisms responsible for these contrasting patterns of VCAM-1 transcriptional activation, contrast studies with VCAM-1, and in vitro binding assays using two adjacent NF-kappa B binding sequences of the VCAM-1 promoter as a DNA probes, suggested requirements of the NF-kB motifs for VCAM-1 transcription and related pathways [492,493,494,495,496,497]. Furthermore, it was shown that the gene regulatory region of VCAM-1 is distinct from the NF-kappa B sites and potentially function as IL-1α -mediated transcriptional repressor within human dermal microvascular endothelial cell. It was concluded that the repressor region conveys IL-1α−dependent, but not TNF α−dependent, inhibition of transcription driven by a heterologous cytokine response on promoter gene [21, 64, 80, 470, 494,495,496,497, 507, 511,512,513,514].

Among pro-angiogenic factors , vascular endothelial growth factor (VEGF ) plays crucial roles in biology of neovascularization and neoplasm growth. In acute inflammation , expression of VEGF is receptor-dependent, interacting with VEGF-R1 (pro-inflammatory for chemotaxis, activation of peripheral monocytes and MMP-9 and vascular hyperpermeability) and VEGF-R2 (anti-inflammatory and inhibition of vascular permeability) processes (Yin-Yang ), respectively. The serum concentration of VEGF in patients is often higher than the plasma level, potentially due to the secretory activity of thrombocytes, which release high amounts of VEGF during blood coagulation. Analyses of relevant data on the role of VEGF in neoplasm growth suggest that VEGF acts through several interdependent pathways involving gelatinase A, decreased in tissue inhibition of endothelial metalloproteases (e.g., MMP 9), altered cell adhesion molecules and selective alterations in IL-1, induction of hypoxia -inducible factor-1 (HIP-1), as well as enhanced expression of NFkB that would lead to alterations of integrity of extracellular matrix and growth of neoplasm . It is possible that the continued expression of MMP-9 that normally signals for wound healing (Yang or termination) of acute inflammation , is viewed by neoplastic tissues as extended signals for wound healing and continued expression of VEGF-R2. The increased activity of VEGF -R2 receptor leads to an enhanced permeability of blood vessels (‘leaky’ vessels) and promotion of neovascularization processes within the neoplastic tissue resulting in proliferation of vascular endothelial cells and decreased ratios of pericytes: endothelial cells. Furthermore, abnormal proliferation of endothelial cells are associated with inhibition of dendritic cell maturation and altered/decreased ratios of DC1/DC2 (TADCs), induction of NO , expression of CAMs , or perhaps altered ratios of M1/M2 (TAM), events that contribute to immune suppression, chronic inflammatory diseases, carcinogenesis and hypoxia -induced angiogenesis [21, 80, 478,479,480,481, 496, 497, 507, 510,511,512,513,514,515,516,517,518,519,520].

Other mediators, chemokines or pro-angiogenic factors whose altered activities are known to contribute to age-associated chronic diseases include (Figs. 3.4, 3.5, and 3.6):

  1. (a)

    Basic fibroblast growth factor (bFGF) interacting through receptor molecules (e.g., FGF-R and FGF-R2);

  2. (b)

    Epidermal growth factor and its receptor (EGFR );

  3. (c)

    Interleukin-8 (IL-8), a chemokine acting through receptor molecules (A/CXCR1 and B/CXCR2) inducing migration of monocytes to neoplastic tissues. High expression levels of IL-8 reported in various types of neoplasms . IL-8 directly correlates with vascularization of proliferating tissue, poor prognosis and advanced growth of cancers such as gastric cancer cells.

7.1 Platelets Contributions in Immunity: Shared Features with Innate Immune Cells

Until recently, platelets were considered as non-immune cell moieties with some immune functions. However, compelling data demonstrate that blood platelets display a number of functions and are special facilitators of acute inflammation contributing effectively in Yin (apoptosis ), and Yang (wound healing ) crosstalks. Platelets originate from myeloid cells and belong to the megakaryocytes (Fig. 3.3). During acute inflammatory processes, platelets play crucial roles in repairing (Yang, anti-inflammatory) the damaged vascular endothelium and stop bleeding and behave as innate immune cells, primarily through expression of PDGF and other wound healing mediators. They also participate in apoptotic events when they recognize a variety of danger signals from infectious agents, including pathogen -(bacteria )- induced acute inflammatory conditions such as sepsis . At least 1000 proteins/factors are reported in platelets activities, many are membrane-bound proteins and actively participate in immune response dynamics such as blood hemostasis, surface molecular shedding as well as pathobiology of diseases [21, 80, 462,463,464,465,466,467,468, 476, 505, 532,533,534,535,536]. For example, platelet-activating factor (PAF) is a potent phospholipid mediator and expressed in response to diverse immunologic and non-immunologic stimuli. In vivo and in vitro studies using PAF receptor antagonists demonstrated PAF involvement in a number of cardiac disorders such as ischemia , infarction and sudden cardiac death. PAF directly affects cardiac tissue by modification of chronotropic and inotropic activity; or indirectly causing coronary artery constriction, modulation of myocardial contractility and induction of arrhythmias by activation of membrane arachidonic acid pathways (e.g., cyclooxygenase-COX , lipooxygenase-LO) and the synthesis of eicosanoids such as thromboxane A2 (TXA2), leukotrienes (LTs) as well as expression of pro-inflammatory cytokines such as TNF-α [21, 80, 476, 505, 532,533,534,535,536].

An overall analyses of data demonstrate that platelets express several receptors with diverse (dual or pleiotropy) functions as other immune cells. The major known functions of platelets that closely resemble the duality of innate immune responses include (details in Chap. 6):

  1. (a)

    Expression of non-mutated ligands (naïve proteins?) and toll-like receptors (TLRs ), through pattern recognition receptor for binding to pathogens or pathogen -derived components (e.g., lipopolysaccharides ) using distinct lipid A moiety that are different from classical receptor molecules (e.g., CRs or FcRs) of innate immune cells.

  2. (b)

    Expression of innate/invariant receptors for the ingestion of a variety of microorganisms through different mechanism of actions for the purpose of destruction or inhibition of pathogenicity;

  3. (c)

    Release a variety of molecular signals for crosstalk with other cells in the tissue microenvironment and/or to influence recruiting cells during an inflammatory process;

  4. (d)

    Polarize and respond to activate cellular machinery upon receiving danger signals to repair tissue damage and wound healing processes;

  5. (e)

    Expression of infection -induced TLRs possesses efficient functions for pathogen -specific production of receptors for antibodies and complement factors and interactions with innate immunity. The roles that CD40-CD40L (ligand) and adhesion molecules play in crosstalk between immune and non-immune cells, under inflammatory conditions, particularly during damage to vascular endothelium and disorders are under extensive studies [476, 505, 532,533,534,535,536].

7.2 Nitric Oxide in Inflammation and Aging

Nitric oxide (NO) is synthesized by vascular endothelial, immune and neuronal cells via NO synthases (NOS). The role of mediator is ubiquitous in controlling the function of almost every, if not all, organ systems in the body. Bacterial or viral products such as lipopolysaccharides (LPS ) induce massive amount of inducible NOS (iNOS) from activated host cells that is toxic to the invading pathogens and inactivation of constituent enzymes, leading to target cell death. Actions of all NO (constituent and inducible) are mediated by the free radical oxidant properties of this soluble gas, as well as by activation of guanylase cyclase (GC), leading to the production of cyclic guanosine monophosphate (cGMP) for immune cell activation (e.g., induction of M2 or TAM) that mediate numerous physiological actions in health and a wide range of chronic diseases and cancer [21, 47, 84,85,86,87,88,89,90, 491, 492, 503, 506, 509, 511, 515, 516,517,518,519,520,521,522,523,524,525,526,527,528,529,530]. For example, NO activates cyclooxygenase and lipoxygenase enzymes leading to the production of physiologically relevant quantities of PGE2 and leukotrienes as well as induction of IRAK-M for tolerance or growth (details in Chap. 6). In the case of iNOS, the massive release of NO , PGE2 and leukotrienes produce toxic effects [85, 491, 492, 503, 506, 509, 511, 515, 516,517,518,519,520,521,522,523,524,525,526,527,528,529,530]. Systemic injection of LPS causes induction of expression of IL-1 β mRNA followed by IL-β synthesis and by induction of iNOS mRNA in a time-course delay of 2 h and 4 h, respectively. The LPS -induced synthesis of NO affects the anterior pituitary and pineal glands, meninges and choroids plexus, regions outside the blood-brain barrier , and shortly thereafter, in hypothalamic regions, such as the temperature-regulating centers, paraventricular nucleus containing releasing and inhibitory hormone neurons, and the arcuate nucleus, a region containing these neurons and axons bound for the median eminence [85,86,87,88]. The question has been raised whether LPS similarly activates production of inflammatory cytokines and iNOS in the cardiovascular system and the gonads. It has been suggested that recurrent infections over the life span play a significant role in producing aging changes in all systems outside the BBB via release of toxic quantities of NO [85, 509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530,531,532,533,534]. NO may be a major factor in the development of coronary heart disease (CHD). Accumulating data indicate a role for the infections in the induction of CHD and indeed patients treated with a tetracycline derivative has 10 times less complications of CHD than their controls [47, 85, 503, 506, 509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530]. Inflammatory conditions induced by infection have been shown to cause activation of iNOS in rats that lead to progression of coronary arteriosclerosis and coronary occlusion. In aging, infections and activation of iNOS may play a role in the decreased secretion of the pituitary and pineal hormones (e.g., melatonin) in anterior pituitary and pineal gland as well as the temperature-regulating centers and the observed loss of thermosensitive neurons [85, 509,510,511,512]. Furthermore, aging and recurrent infection -induced iNOS in the paraventricular nucleus may cause the decreased nocturnal secretion of growth hormone (GH) and prolactin, leading to the destruction of luteinizing hormone-releasing hormone (LHRH), neurons that follow decreased genesis of gonadotropins. Persistent infections (unresolved inflammation) in aging may play a role in the observed increases in the numbers of brain astrocytes expressing IL-1β in older patients [85, 509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530,531,532,533,534,535,536,537,538]. Published data also suggest that IL-1 and products of NO activity accumulate around the plaques in Alzheimers’ patients. During World War I, a role for activation of iNOS was suggested in early onset of Parkinson disease, coupled with aging process, damaging the survival of cells adjacent to substantia nigra dopaminergic neurons as the result of flu-induced encephalitis. It should be noted that the pathology of the central nervous system (CNS) in patients with AIDS bears striking resemblance to aging biological changes, and may also be largely caused by the action of iNOS. Antioxidants , such as melanin, vitamins C, D, E, probably play important acute and chronic roles in reducing or eliminating the oxidant damage produced by NO [47, 85, 503, 506, 509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530].

8 Autophagy and Mitophagy in Inflammation and Aging

Among numerous biological alterations that occur under oxidative stress and aging, the body’s ‘self eating’ processes provided through cellular lysosome, mitochondria and Golgi membrane recycling pathways for degradation and regeneration of proteins and lipids, termed autophagy (macroautophagy) and mitohormesis play crucial roles in maintenance of immunity, physiology and metabolism of tissues and during immunosenescence and chronic diseases. Mitochondrial dysfunction (mitophagy ) has been linked to a number of age-associated or chronic health conditions, including migraine, cardiovascular and neurodegenerative diseases, sarcopenia, cancer, infertility, kidney and liver diseases, drug toxicities and related illnesses [21, 23, 30, 66, 75, 80, 91, 100, 102, 110,111,112,113,114,115,116,117,118,119,120, 148, 149, 154,155,156,157,158,159,160,161,162,163,164,165,166,167, 275,276,277, 510, 511, 542,543,544,545,546,547,548,549,550,551,552,553,554,555,556,557,558,559,560,561,562,563,564,565,566,567,568,569,570,571,572,573,574,575,576,577,578,579,580,581,582,583,584]. Relevant data indicate that the key biochemical functions of mitochondria are beyond its physiological roles as the energy power plant of the body’s tissues and cells. In recent decades, the biology of mitochondria has been the focus of active basic research and clinical studies and as potential target for drug development and prevention for a number of pathological and chronic conditions including aging process and cancer (details in Chaps. 2 and 6) (Fig. 3.7) [21, 23, 30, 66, 75, 80, 91, 100, 102, 110,111,112,113,114,115,116,117,118,119,120, 156, 159, 160, 164, 165, 275,276,277, 510, 511, 543,544,545,546,547,548].

Fig. 3.7
figure 7

Proposed mechanisms of mitochondria dysfunction. (1) Mitochondrial DNA (mDNA) mutation caused by free radical damage; (2) Kreb’s cycle decreased efficiency due to inadequate Kreb’s cycle intermediates; (3) Respiratory chain defect due to enzyme and substrate alteration; and (4) Membrane Disorganization and loss of fluidity (Reproduced from Rustin et al. ‘Defective mitochondria, free radicals, cell death-Reality or myth-ochondria’. Mech Age Develop, Ref. [75])

Full size image

Observations on the association of defects in energy metabolism in cancer cells in relationship with respiration (oxidative phosphorylation ) and the abnormal rates of aerobic glycolysis for ATP synthesis that originally reported by Otto Warburg , led to mitochondrial injury (mitophagy ) concept [557,558,559,560,561,562]. Since these important observations research in metabolism of cancer cells and the role that mitochondria play in cancer growth extended to the presentation of two well-known hypotheses of ‘Crabtree effect’ and the ‘Pasteur effect’ that may be defined as the following interdependent (cause and effect) biological events that would satisfy tumor growth [21, 80, 561, 565, 569, 578,579,580,581,582]:

  1. (a)

    Crabtree Effect: the tumor cells trigger the competitive inhibition of oxidative phosphorylation (respiration ) for phosphate groups (Pi) and ADP , by glycolysis for their enhanced growth requirements;

  2. (b)

    Pasteur Effect: the tumor cells induce inhibition of glycolysis by elevated oxygen concentration.

These concepts argue that cancer cells have higher rates of consumption for either oxygen or glucose, when concentration of the either nutrient is reduced in the microenvironment of cancerous tissue. The concepts suggest the survival adaptability of cancer cell metabolism in adjusting to their microenvironment under the following conditions that are toxic to normal cell survival:

  1. (a)

    Increased mutations or alterations and damage in mitochondrial DNA ;

  2. (b)

    Elevation of hexokinase production;

  3. (c)

    Lysis or loss of mitochondrial cristae structures and altered mitochondrial protein and lipid content;

  4. (d)

    Potential utilization of mitochondrial cardiolipin as additional sources of energy;

Furthermore, as analyses of recent data suggest cancer cell mutations and dysregulation of pathways for expression of PI3K /Akt and the altered balance in the activity of c-MYC, HIF, or p53 alter glucose and amino acids transport and metabolism [21, 80, 177, 438, 483, 544,545,546,547, 561, 565, 569,570,571,572,573,574,575,576,577, 582]. The content and composition of cardiolipin, a key mitochondrial lipid located in the inner membrane of mitochondria, necessary for efficient cellular oxidative phosphorylation (respiration ) or maintenance of chemiosmosis demonstrated to be abnormal in cancer cells. While details of reported data on the role of mitochondria and inflammation in diseases of aging are debatable and not well understood, it is likely that acute inflammation initially causes a burst of energy (ATP ) in mitochondria of activated immune cells, to generate oxidants and toxins during apoptosis (Yin). In the process cardiolipin molecules oscillates/moves from the inner to outer mitochondrial membrane, apparently to facilitate the acute inflammatory processes for termination or wound healing (Yang) events and to prevent further oxidative metabolism , contributing to the protective mechanisms of immunity [21, 23, 80].

Validation of the above integrated concepts awaits systematic studies of the relationships between bioenergetics of mitochondria during acute and chronic inflammatory processes, and better understanding of the bases for dysregulated protein recycling pathways (autophagy ) and the roles that genetics and epigenetics play in health or disease processes to be beneficiary for prevention or treatment of chronic diseases.

9 Hormonal, Metabolic and Lipid Adaptations-Rearrangements in Aging

Multiple and diverse roles of important hormones (e.g., estrogen, progesterone, insulin , glucagons, androgen, andosterone, testosterone, thyroxine, glucocorticoids, mineralcorticoids, dehydroepiandosterone-DHEA) and hormone-like growth factors (e. g., IGF-1, FGF , EGF , VEGF ) on the regeneration and function of organ systems and tissue physiology, development and metabolism in health and age-associated diseases have been extensively documented [21,22,23,24,25,26,27, 30, 50, 58, 64, 77, 80, 102, 103, 111, 128, 176, 247, 271, 540, 547, 585,586,587,588,589,590,591,592,593,594,595,596,597,598,599,600,601,602,603,604,605,606,634]. The influence of these important hormones and growth factors in the biology of aging tissues (e.g., neurogenesis, myelination, cognition, bone, immunity, metabolism ) in the induction of chronic diseases (e.g., diabetes, vascular complications, cardiovascular diseases, atherosclerosis, osteoporosis, Alzheimer’s and many site-specific cancers ) also have been the focus of many recent studies (Figs. 3.1 and 3.2). For example, the age-associated hormonal alterations on thymic atrophy and associated declines in the genesis of subsets of T cells, particularly peripheral T cells have been linked to immune dysfunction , cell death and immunosenescence [23, 25, 131,132,133,134].

In general, hormones including gonadal and sex steroids (e.g., estrogen, androgens, testosterone, progerstrone), DHA/DHEA, insulin or parathyroid hormones (e.g., 1–25 dihydroxy vitamin D, and calcitonin) play crucial roles in the regulations of a wide range of physiological functions in the body such as reproductive systems, organogenesis, fluid homeostasis, bone structure, membrane and intracellular signaling pathways, metabolic and immune responses to stress. The roles that these hormones play, to varying degrees on the physiology, function and remodeling of bone, neuronal function, myelination and neurogeneration of brain and CNS and/or membrane-associated fatty acid metabolism have been extensively studied in experimental models of diseases and in human subjects [21, 23, 58, 80, 590,591,592,593,594,595,596,597,598,599, 602,603,604,605,606,607,608,609,610,611,612,613,614,615,616,617,618,619,620,621,622]. Details on the role of the hormones in health and diseases are beyond the scope of this book. A brief overview of some of the known function of hormones under the influence of oxidative stress and age-associated diseases should help understand the common links in the biology of aging. For example, changes in estrogen or testosterone are associated with increased production of pro-inflammatory cytokines; alterations in bone resorption and remodeling, and changes in essential fatty acid metabolism as contributing factors in osteoporosis and other age-associated illnesses such as atherosclerosis or cancer. Furthermore, insulin deficiency and glucose toxicity (hyperglycemia), or insulin-induced expression of inflammatory mediators such as NF-kB and Ikappa B kinase (IKK-beta, encoded by IKbKb), or surface proteins (e.g., CD40L) in platelets’, adhesion molecules (e.g., VCAM-1) on hepatocytes, endothelial or myeloid cells have been reported. Details of the role that insulin deficiencies play in insulin-dependent (e.g., muscle, liver, adipocytes ) or insulin -independent tissues (e.g., vasculature , kidney, nerves, retina, RPE, lens) as well as, the influence of increased non-enzymatic glycosylation of proteins in alterations of functions of important proteins or metabolites has been extensively studied [21, 23, 58, 64, 77, 102, 111, 271, 540, 547, 548, 598]. A closer examination of the available data on a variety of cytokines (e.g., TNF-α, ILs, VEGF ) and receptor molecules on the endogenous hormones and hormone-like factors such as cortisol, epinephrine, neurotransmitters (e.g., norepinephrine) or melatonin, which also contribute to the growth and immune responses, suggest that aging process elevates the circadian rhythm of these factors and the observed pathophysiological responses. The overall responses are suggestive of compensatory sympathetic outflow increases that elevate norepinephrine levels by activation of adrenoceptors (α & β)-stimulation of the heart, vasculature , kidney and significant changes in the heart rate that influence cardiac output, peripheral vascular resistance, renal blood flow or urine output. In addition, the effect of age on response to dexamethasone treatment among the control group supports the hypotheses that the sensitivity of glucocorticoids negative feedbacks decrease with age [21, 70, 80, 251, 589]. Whether these effects reflect the stress-induced down-regulation of pituitary corticotrophin releasing factor (CRF) receptors and/or accumulation of mismatched inflammatory mediators and changes in the circadian nature of body’s biology (positive and negative feedback control mechanisms or Yin and Yang of immunity) remain to be understood. Other biological systems with important potential pleiotropic roles are the suppressor molecule SIRT1 and melatonin-related processes as clock proteins in facilitating cellular and metabolic dynamics of sensing and controlling the induction of senescence and carcinogenesis [21, 74, 122, 526, 619, 620].

9.1 Inflammation-Induced Sarcopenia or Cachexia in Aging

Sarcopenia or muscle loss (waste) in aging has multifactorial origins, involving activities of neuronal , immunological and physiological pathways [21, 23, 80, 146, 199, 291, 346, 347, 551,552,553, 575, 628]. Analyses of related data including cancer targeted drug-induced cachexia or sarcopenia suggest that sarcopenia is a smoldering inflammatory dynamics, driven by mismatched expression and co-expression of mediators and accelerated rate of unresolved inflammation (immune tsunami or immunological chaos) similar to other diseases of aging including arthritis or cancer affecting different organ systems. The severe conditions resemble the life-threatening effects of cancer ‘targeted’ drugs and induction of cachexia or aneroxia (details in Chap. 6) [21, 23, 80]. The overall contributing factors in the complications of age-associated sarcopenia or cachexia include:

  1. (a)

    Changes in the anabolic hormones such as DHA, glucocorticoids, thyroxine, insulin , estrogen, testosterone and related receptor proteins;

  2. (b)

    Loss of alpha-motor neuron input, decreased intake of dietary protein, and decline in physical activity;

  3. (c)

    Associated changes in glucocorticoid negative feedback inhibition of hypothalamic CRF and pituitary ACTH;

  4. (d)

    Elevated levels of interleukin-6 and C-reactive protein ;

  5. (e)

    Sarcopenic obesity often displays inflammatory burden due to continued activation of adipocytes and associated expression of adipokines.

There are debates whether sarcopenia is a distinct feature of a disease or it is a milder and evolving form of cachexia or anorexia observed in older adults. Furthermore, the beneficiary roles of hormones such as dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS, a reservoir for DHEA) which are antioxidants and weak androgens and primarily produced by adrenal gland, have been reported in treatment of such metabolic disorders (e.g., diabetes or hepatic injury) or longevity and prevention of cancer. Potential recommended interventions for sarcopenia include nutritional supplements, physical activity/resistance exercise, caloric restriction , anabolic hormones , anti-inflammatory agents, vitamin E and other antioxidants [21, 23, 80, 97,98,99, 139, 346, 551, 553].

9.2 Fatty Acid (Lipid) Biology in Inflammation and Aging

Long-chain polyunsaturated fatty acids (essential fatty acids-FAs) including membrane arachidonic acid (AA) metabolites such as prostaglandins (e.g., PGI2/PGF-1α, PGD, PGE2 ), leukotrienes (e.g., LT4, LTC), phosphatidylinositol (PI), phosphatidylserine (PS) together with their respective receptors and enzymes (e.g., COX , LO , phospholipases A, B and C, leukotriene synthases) play crucial roles in regulation, metabolism and function of tissues. For example, membrane fatty acids are involved in a wide range of signal transduction mechanisms and crosstalk during immune and hormonal responses, vasculogenesis and vascular toning, bone remodeling and function in health and diseases of aging [21,22,23,24,25,26,27, 80, 87, 157, 153, 287, 370, 420, 441, 450, 505, 544, 589, 621]. Aging-associated thymus involution along with oxidative stress and certain life styles (e.g., smoking, heavy alcohol consumption) are factors associated with increased levels of pro-inflammatory mediators (e.g., IL-1, TNF-σα, IL-6) and decreased body’s capacity to metabolize and convert precursor of FAs into polyunsaturated FAs that could lead to physiological changes such as decreased in bone mass, resorption and remodeling and impaired calcium balance, alterations of osteoblastogenesis, osteoclastogenesis, and functions of osteoblast and osteoclast during menopause, as well as rheumatoid arthritis. Bone and vascular remodeling and function are controlled by activation of a sophisticated membrane-lipid complex interactions involving intracellular soluble form of ligands and inflammatory mediators [e.g., receptor-activator of nuclear-kappa B (RANK) and ligand binding (RANKL), decoy receptor proteins and bone-specific osteoprotegrin (OPG)] that are essential for differentiation and activation of osteoclasts [192, 283, 408, 417, 434, 493, 575, 602].

10 Concluding Remarks

The increased rate of population among healthy older individuals around the globe suggests that the aging process is not necessarily associated with illnesses. Older people can lead a healthy, active and productive life well beyond the current standard age of retirement that is set at 65–70 years. However, longevity and extensive inflammatory response alterations in the pathways of immune and non-immune networks, particularly the vascular system, seem to be the principal common links in many age-associated chronic health problems such as asthma, hypertension , autoimmune and neurodegenerative diseases, diabetes and cardiovascular complications, stroke, neuronal dysfunctions, Alzheimer’s , Parkinson and site-specific cancers . Aging process itself cause minor or major alterations in the function of immune and non-immune systems that are the bases for altered inflammatory responses to various old and new stimuli. It should be emphasized that the loss of effective immunity is the combined changes of the balance between the biphasic response profiles (two biologically opposing arms) of acute inflammation , initiated by activation of immune cells and facilitated by negative and positive factors of vasculature (angiogenic and antiangiogenic mediators), oxido-redox potentials (oxidants and anti-oxidants ), as well as, dysregulated dual capacities of metabolic and neuronal pathways.

The second laws of thermodynamics and physics may apply to the body’s growth dynamics from fetus development to the aging process. Here we assume that in a normal healthy adult effective immunity conducts orchestration of a fascinating successful and orderly network of positive and negative chemical/biological signals (biological control switches) that constitutes the Yin-Yang of self-terminating acute inflammation for protecting the body against exposures to all potential hazards throughout life. However, biological and immunological rearrangements that occur in organ systems during normal aging are associated with decays or retardation, to varying degrees, of the ordered duality of Yin-Yang that would create general biological chaos. Recently, we hypothesized a concept specifically related to the role that chronic inflammation-(oxidative stress)-induced ‘immunological chaos’ or ‘immune tsunami ’ damages to the architectural integrity and function of tissues toward retardation or altered dynamics of immunity in the direction of tissue necrosis or neoplasia [21,22,23,24,25,26,27, 80]. It is likely that the type and extent of vulnerability of an organ or tissue toward the drifts in the three fundamental systems of genomic stability, immune cells and oxidative stress determine the outcomes of a particular disease process. For example, loss of immunity and altered vascular integrity, including changes in oxido-redox balance in tissues that are immune-privileged (e.g., blood brain barrier or CNS ) could result in diverse manifestations of neurodegenerative diseases such as the stroke, Alzheimer’s , Parkinson or even brain tumors. This takes into consideration of the anatomical barriers loss (BBB ) and biological differences of the brain architectural structure (e.g., vasculature , glial and neuronal tissue) and function within the oxidative-sensitive tissues of the brain, compared with those tissues that are classically known as immune-responsive (e.g., epithelial, endothelial, vasculature ).

Experimental manipulations that slow down aging, such as dietary restriction and result in promotion of immunity are proposed to increase oxidative stress resistance and longevity . Strategies for maintaining the pleiotropic roles of antigen presenting cells (APCs ) are highly desirable targets as these cells are responsible for enhancing and preserving the T cell responses during the aging process. It is noteworthy that modulations of T cell differentiation have limited capacity after puberty. Therefore, stabilizing the duality of innate (APCs ) immune cell responses at APC-T cell interface could prove to be a key in reversing impaired immune function.

Significant improvement of health, particularly for the older population ultimately comes from better understanding of the complex molecular and cellular processes that are collectively involved in declines of immunity during aging. The future directions for systematic studies of the heterogeneities of the biological systems would require constructing a useful ‘roadmap’ that identifies the interrelationships between inflammation and a wide range of biological events that are considered co-morbidity and co-mortality risk factors in increasing the genesis and progression of chronic illnesses. Developing a ‘roadmap’ to identify the key biological control mechanisms that govern the biology of aging process is a timely, challenging and important undertaking for the scientific community toward improving the health of growing population around the world.

11 Author’s Personal Note

The current combination of economic burden of sick-care to the society and the increased population of older adults around the globe require making conscience decisions that the public deserves switching to a culture of healthcare for a more productive society, particularly in the USA. As reflected throughout this book, a personal goal of the author is to continue these challenging scientific and professional attempts for making professionals and public to appreciate that the mission of public health should not be maintenance of costly ‘sick-care’ that only benefit the medical/cancer establishment and associates in big pharma and food industry.

There is a need to switch this wasteful culture of ‘sick care’ to the culture of ‘health care’ where prevention of diseases outweighs the therapeutic approaches.

Immunity in Health and Disease

Effective immunity is crosstalk between the molecular village of negative and positive (Yin-Yang ) signals that guard the body for maintaining health. However, a few bugs or aging process can disturb this amazingly orchestrated and secretively successful molecular operation to make us sick!

Love will draw an elephant through a key-hole. (Samuel Richardson)