Skip to main content
SpringerLink
Log in

Age-Related Dysfunctions: Evidence and Relationship with Some Risk Factors and Protective Drugs

  • Phenoptosis
  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The theories interpreting senescence as a phenomenon favored by natural selection require the existence of specific, genetically determined and regulated mechanisms that cause a progressive age-related increase in mortality. The mechanisms defined in the subtelomere–telomere theory suggest that progressive slackening of cell turnover and decline in cellular functions are determined by the subtelomere–telomere–telomerase system, which causes a progressive “atrophic syndrome” in all organs and tissues. If the mechanisms underlying aging-related dysfunctions are similar and having the same origin, it could be hypothesized that equal interventions could produce similar effects. This article reviews the consequences of some factors (diabetes, obesity/dyslipidemia, hypertension, smoking, moderate use and abuse of alcohol) and classes of drugs [statins, angiotensin-converting enzyme (ACE) inhibitors, sartans] in accelerating and anticipating or in counteracting the process of aging. The evidence is compatible with the programmed aging paradigm and the mechanisms defined by the subtelomere–telomere theory but it has no obvious discriminating value against the theories of non-programmed aging paradigm. However, the existence of mechanisms, determined by the subtelomere–telomere–telomerase system and causing a progressive age-related decline in fitness through gradual cell senescence and cell senescence, is not justifiable without an evolutionary motivation. Their existence is expected by the programmed aging paradigm, while is incompatible with the opposite paradigm.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ACE-I:

angiotensin-converting enzyme inhibitor

AD:

Alzheimer’s disease

AMD:

age-related macular degener-ation

ARB:

angiotensin receptor blocker, or AT1 (angiotensin II receptor type 1) antagonist, or sartan

EPC:

endothelial progenitor cell

PCD:

programmed cell death

PD:

Parkinson’s disease

References

  1. Libertini, G. (1988) An adaptive theory of the increasing mortality with increasing chronological age in populations in the wild, J. Theor. Biol., 132, 145–162.

    Article  CAS  PubMed  Google Scholar 

  2. Finch, C. E. (1990) Longevity, Senescence, and the Genome, The University of Chicago Press, Chicago.

    Google Scholar 

  3. Hill, K., and Hurtado, A. M. (1996) Ache Life History, Aldine De Gruyter, New York.

    Google Scholar 

  4. Ricklefs, R. E. (1998) Evolutionary theories of aging: con-firmation of a fundamental prediction, with implications for the genetic basis and evolution of life span, Am. Nat., 152, 24–44.

    Article  CAS  PubMed  Google Scholar 

  5. Nussey, D. H., Froy, H., Lemaitre, J. F., Gaillard, J. M., and Austad, S. N. (2013) Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology, Ageing Res. Rev., 12, 214–225.

    Article  PubMed  Google Scholar 

  6. Medvedev, Z. A. (1990) An attempt at a rational classifica-tion of theories of ageing, Biol. Rev. Camb. Philos. Soc., 65, 375–398.

    Article  CAS  PubMed  Google Scholar 

  7. Libertini, G., Rengo, G., and Ferrara, N. (2017) Aging and aging theories, J. Gerontol. Geriatrics, 65, 59–77.

    Google Scholar 

  8. Libertini, G. (2008) Empirical evidence for various evolu-tionary hypotheses on species demonstrating increasing mortality with increasing chronological age in the wild, Sci. World J., 8, 182–193.

    Article  Google Scholar 

  9. Libertini, G. (2015) Non-programmed versus programmed aging paradigm, Curr. Aging Sci., 8, 56–68.

    Article  PubMed  Google Scholar 

  10. Kuhn, T. S. (1962) The Structure of Scientific Revolutions, The University of Chicago Press, Chicago.

    Google Scholar 

  11. Hayflick, L. (2007) Entropy explains aging, genetic deter-minism explains longevity, and undefined terminology explains misunderstanding both, PLoS Genet., 3, e220, doi: 10.1371/journal.pgen.0030220

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Libertini, G. (2015) Phylogeny of aging and related phenoptotic phenomena, Biochemistry (Moscow), 80, 1529–1546.

    Article  CAS  Google Scholar 

  13. Travis, J. M. (2004) The evolution of programmed death in a spatially structured population, J. Gerontol. A Biol. Sci. Med. Sci., 59, 301–305.

    Article  PubMed  Google Scholar 

  14. Skulachev, V. P., and Longo, V. D. (2005) Aging as a mito-chondria-mediated atavistic program: can aging be switched off? Ann. N. Y. Acad. Sci., 1057, 145–164.

    Article  CAS  PubMed  Google Scholar 

  15. Martins, A. C. (2011) Change and aging senescence as an adaptation, PLoS One, 6, e24328, doi: 10.1371/journal.pone.0024328.

    Article  CAS  Google Scholar 

  16. Jiang-Nan, Y. (2013) Viscous populations evolve altruistic programmed ageing in ability conflict in a changing envi-ronment, Evol. Ecol. Res., 15, 527–543.

    Google Scholar 

  17. Mitteldorf, J., and Martins, A. C. (2014) Programmed life span in the context of evolvability, Am. Nat., 184, 289–302.

    Article  PubMed  Google Scholar 

  18. Skulachev, V. P. (1999) Phenoptosis: programmed death of an organism, Biochemistry (Moscow), 64, 1418–1426.

    CAS  Google Scholar 

  19. Libertini, G. (2012) Classification of phenoptotic phenomena, Biochemistry (Moscow), 77, 707–715.

    Article  CAS  Google Scholar 

  20. Olshansky, S. J., Hayflick, L., and Carnes, B. A. (2002) Position statement on human aging, J. Gerontol. A Biol. Sci. Med. Sci., 57, B292–B297.

    Article  PubMed  Google Scholar 

  21. Hayflick, L. (2007) Biological aging is no longer an unsolved problem, Ann. N. Y. Acad. Sci., 1100, 1–13.

    Article  CAS  PubMed  Google Scholar 

  22. Kirkwood, T. B., and Melov, S. (2011) On the pro-grammed/non-programmed nature of ageing within the life history, Curr. Biol., 21, R701–707.

    Article  CAS  PubMed  Google Scholar 

  23. De Grey, A. D. (2015) Do we have genes that exist to hasten aging? New data, new arguments, but the answer is still no, Curr. Aging Sci., 8, 24–33.

    Article  PubMed  Google Scholar 

  24. Gladyshev, V. N. (2016) Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environ-mental, and stochastic processes, Aging Cell, 15, 594–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kowald, A., and Kirkwood, T. B. (2016) Can aging be pro-grammed? A critical literature review, Aging Cell, 15, 986–998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mitteldorf, J. (2013) Telomere biology: cancer firewall or aging clock? Biochemistry (Moscow), 78, 1054–1060.

    Article  CAS  Google Scholar 

  27. Fossel, M. B. (2004) Cells, Aging and Human Disease, Oxford University Press, New York.

    Google Scholar 

  28. Libertini, G. (2009) The role of telomere–telomerase system in age-related fitness decline, a tameable process, in Telomeres: Function, Shortening and Lengthening ( Mancini, L., ed.) Nova Science Publ. Inc., New York, pp. 77–132.

    Google Scholar 

  29. Libertini, G. (2014) The programmed aging paradigm: how we get old, Biochemistry (Moscow), 79, 1004–1016.

    Article  CAS  Google Scholar 

  30. Libertini, G., and Ferrara, N. (2016) Aging of perennial cells and organ parts according to the programmed aging paradigm, Age (Dordr.), 38, 1–13.

    Article  Google Scholar 

  31. Libertini, G. (2009) Prospects of a longer life span beyond the beneficial effects of a healthy lifestyle, in Handbook on Longevity: Genetics, Diet & Disease (Bentely, J. V., and Keller, M., eds.) Nova Science Publishers Inc., New York, pp. 35–96.

    Google Scholar 

  32. Goldsmith, T. C. (2008) Aging, evolvability, and the indi-vidual benefit requirement; medical implications of aging theory controversies, J. Theor. Biol., 252, 764–768.

    Article  PubMed  Google Scholar 

  33. Olovnikov, A. M. (2015) Chronographic theory of develop-ment, aging, and origin of cancer: role of chronomeres and printomeres, Curr. Aging Sci., 8, 76–88.

    Article  CAS  PubMed  Google Scholar 

  34. Skulachev, M. V., and Skulachev, V. P. (2014) New data on programmed aging–slow phenoptosis, Biochemistry (Moscow), 79, 977–993.

    Article  CAS  Google Scholar 

  35. Moyzis, R. K., Buckingham, J. M., Cram, L. S., Dani, M., Deaven, L. L., Jones, M. D., Meyne, J., Ratliff, R. L., and Wu, J. R. (1988) A highly conserved repetitive DNA sequence (TTAGGG)n, present at the telomeres of human chromosomes, Proc. Natl. Acad. Sci. USA, 85, 6622–6626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Blackburn, E. H. (1991) Structure and function of telomeres, Nature, 350, 569–573.

    Article  CAS  PubMed  Google Scholar 

  37. Olovnikov, A. M. (1971) Principle of marginotomy in template synthesis of polynucleotides, Dokl. Biochem., 201, 394–397.

    Google Scholar 

  38. Olovnikov, A. M. (1973) A theory of marginotomy: the incomplete copying of template margin in enzyme synthesis of polynucleotides and biological significance of the problem, J. Theor. Biol., 41, 181–190.

    Article  CAS  PubMed  Google Scholar 

  39. Greider, C. W., and Blackburn, E. H. (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts, Cell, 43, 405–413.

    Article  CAS  PubMed  Google Scholar 

  40. Van Steensel, B., and de Lange, T. (1997) Control of telo-mere length by the human telomeric protein TRF1, Nature, 385, 740–743.

    Article  PubMed  Google Scholar 

  41. Hayflick, L., and Moorhead, P. S. (1961) The serial cultivation of human diploid cell strains, Exp. Cell Res., 25, 585–621.

    Article  CAS  PubMed  Google Scholar 

  42. Hayflick, L. (1965) The limited in vitro lifetime of human diploid cell strains, Exp. Cell Res., 37, 614–636.

    Article  CAS  PubMed  Google Scholar 

  43. Gottschling, D. E., Aparicio, O. M., Billington, B. L., and Zakian, V. A. (1990) Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription, Cell, 63, 751–762.

    Article  CAS  PubMed  Google Scholar 

  44. Blackburn, E. H. (2000) Telomere states and cell fates, Nature, 408, 53–56.

    Article  CAS  PubMed  Google Scholar 

  45. Ben-Porath, I., and Weinberg, R. (2005) The signals and pathways activating cellular senescence, Int. J. Biochem. Cell Biol., 37, 961–976.

    Article  CAS  PubMed  Google Scholar 

  46. Klapper, W., Heidorn, K., Kuhne, K., Parwaresch, R., and Krupp, G. (1998) Telomerase activity in “immortal” fish, FEBS Lett., 434, 409–412.

    Article  CAS  PubMed  Google Scholar 

  47. Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., and Wright, W. E. (1998) Extension of lifespan by introduction of telomerase into normal human cells, Science, 279, 349–352.

    Article  CAS  PubMed  Google Scholar 

  48. Van Deursen, J. M. (2014) The role of senescent cells in ageing, Nature, 509, 439–446.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Beausejour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., and Campisi, J. (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways, EMBO J., 22, 4212–4222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Libertini, G. (2013) Evidence for aging theories from the study of a hunter-gatherer people (Ache of Paraguay), Biochemistry (Moscow), 78, 1023–1032.

    Article  CAS  Google Scholar 

  51. Rando, T. A., and Wyss-Coray, T. (2014) Stem cells as vehi-cles for youthful regeneration of aged tissues, J. Gerontol. A Biol. Sci. Med. Sci., 69, Suppl. 1, S39–S42.

    Article  PubMed Central  Google Scholar 

  52. Mistriotis, P., and Andreadis, S. T. (2017) Vascular aging: molecular mechanisms and potential treatments for vascular rejuvenation, Ageing Res. Rev., 37, 94–116.

    Article  CAS  PubMed  Google Scholar 

  53. Libertini, G., and Ferrara, N. (2016) Possible interventions to modify aging, Biochemistry (Moscow), 81, 1413–1428.

    Article  CAS  Google Scholar 

  54. Hill, J. M., Zalos, G., Halcox, J. P., Schenke, W. H., Waclawiw, M. A., Quyyumi, A. A., and Finkel, T. (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk, N. Engl. J. Med., 348, 593–600.

    Article  PubMed  Google Scholar 

  55. Wilson, P. W., Castelli, W. P., and Kannel, W. B. (1987) Coronary risk prediction in adults (the Framingham Heart Study), Am. J. Cardiol., 59, 91–94G; [Erratum], Am. J. Cardiol., 1987, 60(13), A11].

    Article  Google Scholar 

  56. Webster, C., and Blau, H. M. (1990) Accelerated age-related decline in replicative life-span of Duchenne muscular dystrophy myoblasts: implications for cell and gene therapy, Somat. Cell. Mol. Genet., 16, 557–565.

    Article  CAS  PubMed  Google Scholar 

  57. Seale, P., Asakura, A., and Rudnicki, M. A. (2001) The potential of muscle stem cells, Dev. Cell, 1, 333–342.

    Article  CAS  PubMed  Google Scholar 

  58. Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., Park, S. H., Thompson, T., Karsenty, G., Bradley, A., and Donehower, L. A. (2002) p53 mutant mice that display early ageing-associated phenotypes, Nature, 415, 45–53.

    Article  CAS  PubMed  Google Scholar 

  59. Geiger, H., and Van Zant, G. (2002) The aging of lympho-hematopoietic stem cells, Nat. Immunol., 3, 329–333.

    Article  CAS  PubMed  Google Scholar 

  60. Su, J. B. (2015) Vascular endothelial dysfunction and phar-macological treatment, World J. Cardiol., 7, 719–741.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Walter, D. H., Rittig, K., Bahlmann, F. H., Kirchmair, R., Silver, M., Murayama, T., Nishimura, H., Losordo, D. W., Asahara, T., and Isner, J. M. (2002) Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells, Circulation, 105, 3017–3024.

    Article  CAS  PubMed  Google Scholar 

  62. Quik, M., Huang, L. Z., Parameswaran, N., Bordia, T., Campos, C., and Perez, X. A. (2009) Multiple roles for nico-tine in Parkinson’s disease, Biochem. Pharmacol., 78, 677–685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Feingold, K. R., and Grunfeld, C. (2016) Cholesterol lowering drugs, in Endotext [Internet] (www.endotext.org).

    Google Scholar 

  64. Cai, R., Yuan, Y., Sun, J., Xia, W., Huang, R., Tian, S., Dong, X., Shen, Y., and Wang, S. (2016) Statins worsen glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners: a meta-analysis, Expert Opin. Pharmacother., 17, 1839–1849.

    Article  CAS  PubMed  Google Scholar 

  65. Liao, J. K., and Laufs, U. (2005) Pleiotropic effects of statins, Annu. Rev. Pharmacol. Toxicol., 45, 89–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li, W., Du, D. Y., Liu, Y., Jiang, F., Zhang, P., and Li, Y. T. (2017) Long-term nicotine exposure induces dysfunction of mouse endothelial progenitor cells, Exp. Ther. Med., 13, 85–90.

    Article  CAS  PubMed  Google Scholar 

  67. Forero, D. A., Gonzalez-Giraldo, Y., Lopez-Quintero, C., Castro-Vega, L. J., Barreto, G. E., and Perry, G. (2016) Meta-analysis of telomere length in Alzheimer’s disease, J. Gerontol. A Biol. Sci. Med. Sci., 71, 1069–1073.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Falah, M., Najafi, M., Houshmand, M., and Farhadi, M. (2016) Expression levels of the BAK1 and BCL2 genes highlight the role of apoptosis in age-related hearing impairment, Clin. Interv. Aging, 11, 1003–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Birch, J., Anderson, R. K., Correia-Melo, C., Jurk, D., Hewitt, G., Marques, F. M., Green, N. J., Moisey, E., Birrell, M. A., Belvisi, M. G., Black, F., Taylor, J. J., Fisher, A. J., De Soyza, A., and Passos, J. F. (2015) DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease, Am. J. Physiol. Lung Cell. Mol. Physiol., 309, L1124–L1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jonassaint, N. L., Guo, N., Califano, J. A., Montgomery, E. A., and Armanios, M. (2013) The gastrointestinal man-ifestations of telomere-mediated disease, Aging Cell, 12, 319–323.

    Article  CAS  PubMed  Google Scholar 

  71. Ueha, R., Ueha, S., Kondo, K., Sakamoto, T., Kikuta, S., Kanaya, K., Nishijima, H., Matsushima, K., and Yamasoba, T. (2016) Damage to olfactory progenitor cells is involved in cigarette smoke-induced olfactory dysfunction in mice, Am. J. Pathol., 186, 579–586.

    Article  CAS  PubMed  Google Scholar 

  72. Das, U. N. (2016) Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions, Arch. Med. Sci., 12, 1142–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Vicente Miranda, H., El-Agnaf, O. M., and Outeiro, T. F. (2016) Glycation in Parkinson’s disease and Alzheimer’s disease, Mov. Disord., 31, 782–790.

    Article  CAS  PubMed  Google Scholar 

  74. Spielman, L. J., Little, J. P., and Klegeris, A. (2014) Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration, J. Neuroimmunol., 273, 8–21.

    Article  CAS  PubMed  Google Scholar 

  75. Han, C., Linser, P., Park, H. J., Kim, M. J., White, K., Vann, J. M., Ding, D., Prolla, T. A., and Someya, S. (2016) Sirt1 deficiency protects cochlear cells and delays the early onset of age-related hearing loss in C57BL/6 mice, Neurobiol. Aging, 43, 58–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yun, J. H., Morrow, J., Owen, C. A., Qiu, W., Glass, K., Lao, T., Jiang, Z., Perrella, M. A., Silverman, E. K., Zhou, X., and Hersh, C. P. (2017) Transcriptomic analysis of lung tissue from cigarette smoke induced emphysema murine models and human COPD show shared and distinct pathways, Am. J. Respir. Cell. Mol. Biol., 57, 47–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sung, I. Y., Park, B. C., Hah, Y. S., Cho, H. Y., Yun, J. W., Park, B. W., Kang, Y. H., Kim, H. C., Hwang, S. C., Rho, G. J., Kim, U. K., Woo, D. K., Oh, S. H., and Byun, J. H. (2015) FOXO1 is involved in the effects of cigarette smoke extract on osteoblastic differentiation of cultured human periosteum-derived cells, Int. J. Med. Sci., 12, 881–890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Carmeli, E., and Reznick, A. Z. (1994) The physiology and biochemistry of skeletal muscle atrophy as a function of age, Proc. Soc. Exp. Biol. Med., 206, 103–113.

    Article  CAS  PubMed  Google Scholar 

  79. Zeng, H., Vaka, V. R., He, X., Booz, G. W., and Chen, J. X. (2015) High-fat diet induces cardiac remodeling and dysfunction: assessment of the role played by SIRT3 loss, J. Cell. Mol. Med., 19, 1847–1856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Scheen, A. J. (2005) Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion? Diabetes Metab., 31, 5S27–5S34.

    Article  CAS  Google Scholar 

  81. Yayama, K., Miyagi, R., Sugiyama, K., Sugaya, T., Fukamizu, A., and Okamoto, H. (2008) Angiotensin II regulates liver regeneration via type 1 receptor following partial hepatectomy in mice, Biol. Pharm. Bull., 31, 1356–1361.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors.

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Independent researcher, member of the Italian Society for Evolutionary Biology, Asti, Italy

    G. Libertini

  2. Department of Medicine and Health Sciences, University of Molise, and Italian Society of Gerontology and Geriatrics (SIGG), 86100, Campobasso, Italy

    G. Corbi

  3. Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy

    M. Cellurale & N. Ferrara

  4. Italian Society of Gerontology and Geriatrics (SIGG), Florence, Italy

    M. Cellurale

  5. Istituti Clinici Scientifici Maugeri IRCCS, SpA SB, Telese Terme (BN), Italy

    N. Ferrara

Authors
  1. G. Libertini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Corbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Cellurale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Ferrara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. Libertini.

Additional information

Conflict of interest. The authors declare no conflict of interest in financial or any other area.

Compliance to ethical norms. This article does not contain any studies with human participants or animals performed by any of the authors.

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 12, pp. 1781–1791.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Libertini, G., Corbi, G., Cellurale, M. et al. Age-Related Dysfunctions: Evidence and Relationship with Some Risk Factors and Protective Drugs. Biochemistry Moscow 84, 1442–1450 (2019). https://doi.org/10.1134/S0006297919120034

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297919120034

Keywords

Search

Navigation