Biology Of Aging
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Contents |
Introduction
- Also see age-related physiological changes.
Notes
- programmed theories vs accumulation of errors
- interaction of genetics with environmental experiences result in gene expression/activation
- cellular senescence (Hayflick phenomenon)
- absence of telomerase & reduction in telomere length with successive cell population doublings limits replicative capacity of cells in culture
- likely represents quiescence & terminal differentiation rather than senescence
- embryonic stem cells may retain telomerase activity
- physical aging
- 70% environmental influence on mean life expectancy
- genetic influence markedly more important in extreme old age ( maximum life span)
- antagonistic pleiotropy
- genetic package to deal with stress
- evolutionary pressure: reproduction vs senescence
- shortage of food pressures for longevity
- need to live longer to successfully reproduce when there is a shortage of food
- increase in size pressure for longevity
- larger animals have survival & reproductive advantage
- reproduction drives survival of species
- cellular changes that lead to longevity may preferentially suppress tumorigenesis
- programmed theories
-
- inability to maintain homeostasis
- death hormone proposed but has NOT been found
- accumulation of errors
- cross-linking, stiffness of tissue
- DNA damage (none identified as associated with aging)
- error catastrophe, the accumulation of errors in genes encoding regulatory proteins (errors NOT in translated sequences)
- wear & tear: infections, stress
- a less rectangular-shaped survival curve expected
- rate of living
- limited energy (genetic + environmental influences)
- mitochondrial damage
- oxidative stress: most marketed theory
- disease models
- disease of accelerated aging
- disease with risk increasing progressively with age
- examples
- delay in progression is key to therapy
- diseases that occur at proscribed age
- Werner's syndrome
- multiple sclerosis
- amyotrophic lateral sclerosis ( ALS)
- Huntington's chorea
- delay in onset is crucial
- Drosophila, manipulations that reduce mortality
- overexpression of antioxidants
- knockout of methusela gene
- partial knockout of indy gene
- mice, manipulations that extend maximum life span
- growth hormone or growth hormone receptor knockouts [4]
- knockout of gene for p66 shc-adaptor protein [5]
- C. elegans
- enhanced expresion of SIR2 gene increases life span
- calorie restriction increases life span in rodents, yeast
- increased mean & maximum life span
- delay in age-related disease
- pharmaceuticals
- high-dose resveratrol mitigates deleterious effect of high-fat diet in mice [7]
- sirolimus ( rapamycin) increases longevity in mice probably by inhibiting mTOR [8]
- Transcriptional changes with aging
- somatic cells in mice
- increased stress response
- induced heat shock response
- decreased energy metabolism
- reduced glycolysis
- mitochondrial dysfunction
- increased neuronal injury
- calorically restricted mice
- increased protein metabolism
- increased synthesis & turnover
- increased energy metabolism
- upregulation of gluconeogenesis & pentose shunt
- increased biosynthesis
- fatty acid synthesis
- nucleotide precursors
- reduced macromolecular damage
- suppression of heat shock factors
- inducible detoxification systems less active
- DNA repair systems less active
- BHLHB9, ASAH2B, HSBP1
- also see evolutionary biology of longevity
More General Terms
Additional Terms
References
- Castle, SC. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- Castle, SC. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 25-28, 2002
- Mobbs, C, Molecular and biologic factors in aging. In: Geriatric Medicine: An Evidence-Based Approach, 4th ed, Cassel CK et al (eds), Springer-Verlag, New York, 2003 Johnson TE Increased life span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 1990; 249:908
- Morris JZ et al, A phosphatidyl inositol 3-OH kinase family member regulating longevity and dipause in Caenorhabditis elegans. Nature 1996; 382:536
- Kimura KD et al, daf-2, an insulin receptor-like gene that regulates longevity and diapause Caenorhabditis elegans. Science 1997 277:942 - Brown-Borg HM et al, Dwarf mice and the ageing process. Nature 1996; 384:33
- Coschigano KT et al, Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 2000; 141:2608 - Migliaccio E et al, The p66shc adaptor protein controls oxidative stress response and life span in mammals [] Nature 1999; 402:309
- Pinkston JM et al, Mutations that increase the life span of C. elegans inhibit tumor growth. Science 2006, 313:971 PMID: [1]
- Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high- calorie diet. Nature. 2006 Nov 1; [Epub ahead of print] <PubMed> PMID: [2] <Internet> [3]
- Miller T Proceedings of the 38th Annual Meeting of the American Aging Association: Integrative Biology: Hormones, Signaling, and Aging. May 29-June 1, 2009, Scottsdale, AZ
- Harrison DE et al Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009 Jul 8 [4]
