Geroscience, Senescence, & Aging
Aging is progressively becoming more understood through research, but aging is still an inevitable fate of practically all living organisms on Earth. Aging is a process of becoming less able to regenerate new tissue, and the loss of regeneration is characterized by slow yet detrimental physiological changes over an organism’s lifetime. A currently hypothesis for these changes over time is antagonistic pleiotropy and is further understood as senescence. Antagonistic pleiotropy was made known by George Williams, and the hypothesis provides a possible explanation for how senescence affects aging (Williams 1957). Cellular senescence has been linked to the development of diseases associated with aging.
The idea of pleiotropy is that a specific gene may be advantageous to the immediate fitness of the organism, but there are other functions of the same gene which may be detrimental to the organism’s health over time. By characterizing pleiotropy scientists are able to potentially promote a healthier and potentially longer life (Elena 2003). Over time cells lose their ability to positively respond to oncogenic stress causing proliferation with senescence. Cellular senescence refers a reduction of mitotic cycle activity, an evolutionary mechanism to combat age-related tumor development, and chronic inflammation (Campisi 2013): research today shows that this age-related cell cycle arrest is practically inevitable, and senescence is promoted by oncogenic stress (Campisi 2007). Tumor suppressor secreted factors from senescent cells is a key to keeping cancer from becoming a disease, and an example is p53 gene regulation (Campisi 2013).
The most common diseases associated with aging are Alzheimer’s, Parkinson’s, Diabetes Dementia, and Cancer. These diseases result from hyperplasia pathogens that give rise decline in function as we age. Examples of these declines are sarcopenia, atherosclerosis, osteoporosis, macular degeneration, pulmonary insufficiency, renal failure, and neurodegeneration (Campisi 2013). Research today seeks to mimic gain of function and loss of function in model organisms to further understand pleiotropy relationship with age-related decline of cellular function. When a loss of function occurs there is inactivity genetic transcription or translation, and a prominent loss of function that results from aging is inability cells to stop proliferation. Cancer often results in a loss of apoptotic secreted factors, or a mutation that results in more proliferation than programmed cell death.
Hyperplasic pathologies are directly associated with aging, and the most deadly Is Cancer. Cancer has been shown to derive from genetic mutations driven by heredity, and chronic stimuli from the external environment (Anand 2008). Cancer development generally takes 5 or 6 decades to develop from the accumulation of DNA damage in Homo sapiens. Studies have shown that mutations involving inoperable transcription factors are known inducers of cancer but this result primarily from lifestyle, and the DNA damage theory of aging (Freitas 2011). Cancers arising from cells are known to arise from mutations affecting anti-growth signals, evading apoptosis, limitless proliferative potential, sustained angiogenesis, tissue invasion, and metastasis (Hanahan 2011). The external environment contributes to the development of cancer by carcinogens and reactive oxidative species.
Combating age-related disease development by modulating senescence and regenerative biology is the future of disease management. Intermittent dosing of senescent cell repressor for disease treatment is currently a plausible approach to antagonizing the development of age-related diseases. The reason for promoting regeneration of cells in old age is reverse senescence, but completely reversing senescence will not be beneficial due to pleiotropy; therefore, a balance between activity and senescence must be maintained throughout the life of an organism by understanding the senescence-associated secretory phenotype (Demaria 2014) (Coppe 2010). We know that senescence is necessary for suppressing tumor formation by suppressing proliferation. The con of senescence is that regenerative abilities of cells and tissues are reduced; further, this indicates that there must be a consistent balance of the activity and senescence in order to combat the main diseases associated with aging.
References
Aging, Cellular Senescence, and Cancer, Judith Campisi, Buck Institute for Research on Aging, Novato, California 94945, Annu. Rev. Physiol. 2013.75:685–705.
Campisi J, d’Adda di Fagagna F. 2007. Cellular senescence: When bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8:729–40
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA Marco Demaria,1 Naoko Ohtani,2 Sameh A. Youssef,3 Francis Rodier,1,9 Wendy Toussaint,4,10 James R. Mitchell,4,11 Remi-Martin Laberge,1 Jan Vijg,5 Harry Van Steeg,6,7 Martijn E.T. Dolle´ ,7 Jan H.J. Hoeijmakers,4 Alain de Bruin,3 Eiji Hara,2 and Judith Campisi1,8,* 1Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Williams G.C. (1957). “Pleiotropy, natural selection, and the evolution of senescence”. Evolution 11: 398–411. doi:10.2307/2406060.
Elena S.F., Sanjuán R. (2003). “Climb every mountain?”. Science 302 (5653): 2074–2075. doi:10.1126/science.1093165
Freitas AA, de Magalhães JP (2011). “A review and appraisal of the DNA damage theory of ageing”. Mutation Research (journal) 728 (1–2): 12–22. doi:10.1016/j.mrrev.2011.05.001. PMID 19594328.
Anand P, Kunnumakkara AB, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (September 2008). “Cancer is a preventable disease that requires major lifestyle changes”. Pharm. Res. 25 (9): 2097–116. doi:10.1007/s11095–008–9661–9. PMC 2515569. PMID 18626751
Hallmarks of Cancer: The Next Generation, Douglas Hanahan1,2,* and Robert A. Weinberg3,* USA DOI 10.1016/j.cell.2011.02.013
The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression Jean-Philippe Coppé1, Pierre-Yves Desprez2,3, Ana Krtolica1, and Judith Campisi1,2 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 Published in final edited form as: Annu Rev Pathol. 2010 ; 5: 99–118. doi:10.1146/annurev-pathol-121808–102144.
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