Which theory of aging best explains why we grow old?
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- The stochastic causative approach propagates that aging is a consequence of the stochastic events of the different hallmarks of aging.
- The pseudo-programmed causative approach propagates that aging is a product of a developmental program that has lost its purpose with time and the random accumulation of harmful events. Basically, it is not solely programmed, nor is it an accumulation of stochastic harmful processes, but resembles antagonistic pleiotropy.
- The programmed causative approach states that aging is programmed (at least partially) and governed by a genetic motif. However, since the experimental reversal is possible, the process of aging is not self-sustaining and requires continuous input from the genetic control mechanism. This genetic motif positively regulates all the processes involved in aging like inflammation and senescence-associated secretory phenotype (SASP). The effects of this control mechanism are attenuated by anti-aging factors like Sirtuin 1 and Forkhead box protein O.
- The stochastic causative, but programmed response approach states that every event that contributes to aging like DNA damage, reactive oxygen species, senescence, apoptosis, etc. is stochastic and their respective counteractive mechanisms are programmed. Moreover, failures of these counteractive mechanisms that accelerate aging are stochastic and they initiate the process of aging. This approach suggests that aging might be irreversible at the organismal level but not at the cellular, tissue, and organ level.
- Deleteriome is a quasi-programmed composite of not only the damage in the classical sense but all the processes that lead to deleterious changes (increased disorder at all levels). Its components influence each other and lead to aging. Rather than individual age-related changes in single cells or organs, the markers of deleteriome are those that represent a plethora of age-related factors at the organismal level simultaneously, for example – the changing DNA methylome and the non-targeted metabolite profiling. Imperfections in biological processes lead to unwanted damage on all levels, from cells to organs. This damage is both programmed (resulting from genes) and stochastic (resulting from physicochemical reactions and the environment). Errors in DNA replication, transcription, translation also lead to some form of damage, which is encoded. This damage will change as the organism ages and also during evolution. Consequently, different kinds of imperfections lead to a huge diversity in damage. Evolution only takes care of the severe kinds of damage and the mild ones (tolerated deleterious processes) accumulate and manifest gradually with age.
Galkin F, Zhang B, Dmitriev SE, Gladyshev VN. Reversibility of irreversible aging. Ageing Res Rev [Internet]. 2019 Jan;49:104–14. https://linkinghub.elsevier.com/retrieve/pii/S156816371830254X
Campisi J. Aging, Cellular Senescence, and Cancer. Annu Rev Physiol [Internet]. 2013 Feb 10;75(1):685–705. http://www.annualreviews.org/doi/10.1146/annurev-physiol-030212-183653
Sapieha P, Mallette FA. Cellular Senescence in Postmitotic Cells: Beyond Growth Arrest. Trends Cell Biol [Internet]. 2018 Aug;28(8):595–607. https://linkinghub.elsevier.com/retrieve/pii/S096289241830059X
McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol [Internet]. 2018 Jan 2;217(1):65–77. https://rupress.org/jcb/article/217/1/65/39207/Senescence-and-aging-Causes-consequences-and
Schmeer C, Kretz A, Wengerodt D, Stojiljkovic M, Witte OW. Dissecting Aging and Senescence - Current Concepts and Open Lessons. Cells (Internet). 2019 Nov 15;8(11):1446. https://www.mdpi.com/2073-4409/8/11/1446
Goldsmith TC. Evolution of aging theories: Why modern programmed aging concepts are transforming medical research. Biochem [Internet]. 2016 Dec 18;81(12):1406–12. http://link.springer.com/10.1134/S0006297916120026
Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal [Internet]. 2012 Apr;24(4):835–45. https://linkinghub.elsevier.com/retrieve/pii/S0898656811003846
Gladyshev VN. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell [Internet]. 2016 Aug;15(4):594–602. http://doi.wiley.com/10.1111/acel.12480
Salminen A, Ojala J, Huuskonen J, Kauppinen A, Suuronen T, Kaarniranta K. Interaction of aging-associated signaling cascades: Inhibition of NF-κB signaling by longevity factors FoxOs and SIRT1. Cell Mol Life Sci [Internet]. 2008 Apr 15;65(7–8):1049–58. http://link.springer.com/10.1007/s00018-008-7461-3
Entropy and hormesis
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Only two theories
- Hyperfunction theory of quasi-programmed aging.
- All other theories, all of them are variations of the same: aging is functional decline caused by accumulation of damages (mostly molecular damages)
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- Programmed Longevity. Aging is the result of a sequential switching on and off of certain genes, with senescence being defined as the time when age-associated deficits are manifested. Dr. Davidovic et al discuss the role of genetic instability in aging and the dynamics of the aging process (1).
- Endocrine Theory. Biological clocks act through hormones to control the pace of aging. Recent studies confirm that aging is hormonally regulated and that the evolutionarily conserved insulin/IGF-1 signaling (IIS) pathway plays a key role in the hormonal regulation of aging. Dr. van Heemst discusses the potential mechanism underlying IIS and the aging process(2).
- Immunological Theory. The immune system is programmed to decline over time, which leads to an increased vulnerability to infectious disease and thus aging and death. It is well documented that the effectiveness of the immune system peaks at puberty and gradually declines thereafter with the advance in age. For example, as one grows older, antibodies lose their effectiveness, and fewer new diseases can be combated effectively by the body, which causes cellular stress and eventual death (3).
- Indeed, the dysregulated immune response has been linked to cardiovascular disease, inflammation, Alzheimer’s disease (AD), and cancer. Although direct causal relationships have not been established for all these detrimental outcomes, the immune system has been at least indirectly implicated (4).