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biology of aging

Also see age-related physiological changes. Notes: Theories of aging 1) antagonistic pleiotropy a) traits that promote development or favor reproductive fitness may be harmful in late life [9] b) evolutionary pressure: reproduction vs senescence 1] shortage of food pressures for longevity - need to live longer to successfully reproduce when there is a shortage of food 2] increase in size a pressure for longevity - larger animals have survival & reproductive advantage 3] reproduction drives survival of species c) cellular changes that lead to longevity may preferentially suppress tumorigenesis d) genetic package to deal with stress e) 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 f) cellular senescence aligns with antagonistic pleiotropy [9] - benefit for tumor suppression early in life might lead to deleterious effects later in life [9] 2) disposable soma theory - organisms age due to an evolutionary trade-off between growth, reproduction, & DNA repair maintenance 3) programmed theories vs accumulation of errors a) interaction of genetics with environmental experiences result in gene expression/activation b) physical aging 1] 70% environmental influence on mean life expectancy 2] genetic influence markedly more important in extreme old age (maximum life span) 4) programmed theories a) autoimmunity: chronic inflammation b) neuroendocrine: 1] inability to maintain homeostasis 2] death hormone proposed but has NOT been found 5) accumulation of errors a) cross-linking, stiffness of tissue b) DNA damage (none identified as associated with aging) - mutation accumulation theory - error catastrophe, the accumulation of errors in genes (mutations) encoding regulatory proteins (errors NOT in translated sequences) c) wear & tear: infections, stress - a less rectangular-shaped survival curve expected c) rate of living 1] limited energy (genetic + environmental influences) 2] mitochondrial damage d) oxidative stress: most marketed theory - free-radical theory - epigenetic oxidative redox shift (EORS) theory [10] - triggered by sedentary behavior - shifts energy metabolism away from mitochondria 6) homeostenosis theory - contraction of reserve capacity with age that manifests as a diminished ability to maintain homeostasis under stress [9] 7) epigenetic modifications theory - a loss of transcriptional integrity - exemplified by differences in histone acetyltransferase & DNA methyltransferase activity between identical twin pairs [9] 8) telomere theory of aging - the life & death of Dolly allegedly support the telomere theory of aging (see Dolly) 9) compression of morbidity theory - processes that improve lifespan also improve healthspan - diseases occur later in life compressing time associated with morbidity * telomere shortening does not play a causal role in aging [13] no evolutionary theory of aging is universally accepted aging did not evolve, longevity evolved Models to test theories of aging 1) disease models a) disease of accelerated aging 1] progeria 2] Werner's syndrome 3] Down's syndrome b) disease with risk increasing progressively with age 2] examples a] cardiovascular disease b] Alzheimer's disease c] Parkinson's disease d] diabetes mellitus, type II e] osteoporosis 3] delay in progression is key to therapy c) diseases that occur at proscribed age 1] Werner's syndrome 2] multiple sclerosis 3] amyotrophic lateral sclerosis (ALS) 4] Huntington's chorea 5] delay in onset is crucial 2) transgenic animals, genetic mutations a) Drosophila, manipulations that reduce mortality - overexpression of antioxidants - knockout of methusela gene - partial knockout of indy gene b) mice, manipulations that extend maximum life span - growth hormone or growth hormone receptor knockouts [4] - knockout of gene for p66 shc-adaptor protein [5] - combination gene therapy (FGF21, alpha-Klotho, & TGF-beta receptor-2) treats multiple age-related diseases in mice including obesity, type 2 diabetes, heart failure, & renal failure [15] c) C. elegans - mutations in AGE-1 & DAP-2 genes reduce mortality d) yeast - enhanced expresion of SIR2 gene increases life span 4) calorie restriction increases life span in rodents, yeast a) increased mean & maximum life span b) delay in age-related disease 5) pharmaceuticals a) high-dose resveratrol mitigates deleterious effect of high-fat diet in mice [7] b) sirolimus (rapamycin) increases longevity in mice probably by inhibiting mTOR [8] Technologies to test theories on aging 1) DNA microarrays 2) proteomics - combinations of proteins indicate the pace of aging in specific organs [18] - adipose tissue, artery, brain, heart, immune tissue, intestine, kidney, liver, lung, muscle, pancreas - accelerated aging in a specific organ correlates with risk for disease in that organ [18] 3) artificial intelligence Transcriptional changes with aging 1) somatic cells in mice a) increased stress response -> induced heat shock response b) decreased energy metabolism 1] reduced glycolysis 2] mitochondrial dysfunction c) increased neuronal injury 1] reinnervation 2] neurite extension & sprouting 2) calorically restricted mice a) increased protein metabolism -> increased synthesis & turnover b) increased energy metabolism -> upregulation of gluconeogenesis & pentose shunt c) increased biosynthesis 1] fatty acid synthesis 2] nucleotide precursors d) reduced macromolecular damage 1] suppression of heat shock factors 2] inducible detoxification systems less active 3] DNA repair systems less active e) calorie restriction appears to exert its benefits on longevity through actions of Sirt1 in the hypothalamus Genes implicated in aging process: 1) BHLHB9, ASAH2B, HSBP1, SIRT1 2) also see evolutionary biology of longevity Cancer & Aging - cancer survivors are subject to an increased rate of aging with associated increase in all-cause & cancer-specific mortality [17]

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age-related physiological changes aging evolutionary biology of longevity geriatrics longevity

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gerontology

References

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  2. Castle, SC. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 25-28, 2002
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  8. 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 http://dx.doi.org/10.1038/nature08221
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  10. Brewer GJ. Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories. Exp Gerontol. 2010 Mar;45(3):173-9. PMID: 19945522
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  13. Simons MJ Questioning causal involvement of telomeres in aging. Ageing Res Rev. 2015 Aug 21 PMID: 26304838
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  15. Davidsohn N, Pezzone M, Vernet A et al A single combination gene therapy treats multiple age-related diseases. Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23505-23511. PMID: 31685628 Free PMC Article
  16. Wikipedia: Disposable soma theory of aging https://en.wikipedia.org/wiki/Disposable_soma_theory_of_aging
  17. Zhang D, Leeuwenburgh C, Zhou D et al Analysis of Biological Aging and Risks of All-Cause and Cardiovascular Disease- Specific Death in Cancer Survivors. JAMA Netw Open. 2022;5(6):e2218183. June 22 PMID: 35731518 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793435
  18. Oh HS et al. Organ aging signatures in the plasma proteome track health and disease. Nature 2023 Dec 6; 624:164. PMID: 38057571 PMCID: PMC10700136 Free PMC article. https://www.nature.com/articles/s41586-023-06802-1