Neurochemical Research

, Volume 33, Issue 12, pp 2444–2471 | Cite as

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

  • Vittorio CalabreseEmail author
  • Carolin Cornelius
  • Cesare Mancuso
  • Giovanni Pennisi
  • Stella Calafato
  • Francesco Bellia
  • Timothy E. Bates
  • Anna Maria Giuffrida Stella
  • Tony Schapira
  • Albena T. Dinkova Kostova
  • Enrico Rizzarelli
Review Article


The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer’s and Parkinson’s diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called “protein conformational diseases”. The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-l-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.


Cellular stress response Redox homeostasis Aging Neurodegenerative disorders Vitagenes Antioxidants 



This work was supported by grants of MIUR, FIRB RBNE03PX83, and FIRB RBRN07BMCT.


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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Vittorio Calabrese
    • 1
    Email author
  • Carolin Cornelius
    • 1
  • Cesare Mancuso
    • 2
  • Giovanni Pennisi
    • 3
  • Stella Calafato
    • 1
    • 4
  • Francesco Bellia
    • 1
  • Timothy E. Bates
    • 5
  • Anna Maria Giuffrida Stella
    • 1
  • Tony Schapira
    • 4
  • Albena T. Dinkova Kostova
    • 6
    • 7
  • Enrico Rizzarelli
    • 1
  1. 1.Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of MedicineUniversity of CataniaCataniaItaly
  2. 2.Institute of PharmacologyCatholic University School of MedicineRomeItaly
  3. 3.Department of NeurosciencesUniversity of CataniaCataniaItaly
  4. 4.University Department of Clinical Neurosciences, Institute of NeurologyUniversity College LondonLondonUK
  5. 5.School of Biomedical SciencesUniversity of NottinghamNottinghamUK
  6. 6.Division of Clinical Pharmacology, Departments of Medicine and Pharmacology and Molecular SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  7. 7.Biomedical Research CentreUniversity of DundeeScotlandUK

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