biology of aging
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Introduction
Also see age-related physiological changes.
Notes
- antagonistic pleiotropy
- traits that promote development or favor reproductive fitness may be harmful in late life[9]
- evolutionary pressure: reproduction vs senescence
- cellular changes that lead to longevity may preferentially suppress tumorigenesis
- genetic package to deal with stress
- 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
- cellular senescence aligns with antagonistic pleiotropy[9]
- benefit for tumor suppression early in life might lead to deleterious effects later in life[9]
- disposable soma theory
- organisms age due to an evolutionary trade-off between growth, reproduction, & DNA repair maintenance
- programmed theories vs accumulation of errors
- interaction of genetics with environmental experiences result in gene expression/activation
- physical aging
- 70% environmental influence on mean life expectancy
- genetic influence markedly more important in extreme old age (maximum life span)
- programmed theories
- autoimmunity: chronic inflammation
- neuroendocrine:
- 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)
- mutation accumulation theory
- error catastrophe, the accumulation of errors in genes (mutations) 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
- free-radical theory
- epigenetic oxidative redox shift (EORS) theory[10]
- triggered by sedentary behavior
- shifts energy metabolism away from mitochondria
- homeostenosis theory
- contraction of reserve capacity with age that manifests as a diminished ability to maintain homeostasis under stress[9]
- epigenetic modifications theory
- a loss of transcriptional integrity
- exemplified by differences in histone acetyltransferase & DNA methyltransferase activity between identical twin pairs[9]
- telomere theory of aging
- the life & death of Dolly allegedly support the telomere theory of aging (see Dolly)
- 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
- 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
- transgenic animals, genetic mutations
- 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]
- 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. elegans
- yeast
- Drosophila, manipulations that reduce mortality
- 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]
Technologies to test theories on aging
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
- reinnervation
- neurite extension & sprouting
- increased stress response
- 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
- calorie restriction appears to exert its benefits on longevity through actions of Sirt1 in the hypothalamus
- increased protein metabolism
Genes implicated in aging process:
- BHLHB9, ASAH2B, HSBP1, SIRT1
- 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]
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 - ↑ 4.0 4.1 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 - ↑ 5.0 5.1 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: https://www.ncbi.nlm.nih.gov/pubmed/16917064
- ↑ 7.0 7.1 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: https://www.ncbi.nlm.nih.gov/pubmed/17086191 <Internet> http://dx.doi.org/10.1038/nature05354
- ↑ 8.0 8.1 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 - ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 10.0 10.1 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: https://www.ncbi.nlm.nih.gov/pubmed/19945522
- ↑ Ljubuncic P, Reznick AZ. The evolutionary theories of aging revisited--a mini-review. Gerontology. 2009;55(2):205-16 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19202326
- ↑ Ludlow AT, Roth SM. Physical activity and telomere biology: exploring the link with aging-related disease prevention. J Aging Res. 2011 Feb 21;2011:790378. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21403893
- ↑ 13.0 13.1 Simons MJ Questioning causal involvement of telomeres in aging. Ageing Res Rev. 2015 Aug 21 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26304838
- ↑ Vijg J. Aging genomes: a necessary evil in the logic of life. Bioessays. 2014 Mar;36(3):282-92. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24464418
- ↑ 15.0 15.1 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: https://www.ncbi.nlm.nih.gov/pubmed/31685628 Free PMC Article
- ↑ Wikipedia: Disposable soma theory of aging https://en.wikipedia.org/wiki/Disposable_soma_theory_of_aging
- ↑ 17.0 17.1 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: https://www.ncbi.nlm.nih.gov/pubmed/35731518 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793435
- ↑ 18.0 18.1 18.2 Oh HS et al. Organ aging signatures in the plasma proteome track health and disease. Nature 2023 Dec 6; 624:164. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38057571 PMCID: PMC10700136 Free PMC article. https://www.nature.com/articles/s41586-023-06802-1