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Which theory of aging best explains why we grow old?

Which theory of aging best explains why we grow old?

By Darko Savic on Jul 26, 2020


According to Schmeer and colleagues, senescence lies in the second category – pseudo-programmed causative approach. However, it is difficult to conclude which category aging falls in. What do you think and why?

Theories of aging

Aging is a phenomenon involving a perpetual increased chance of dying and/or a decrease in the functionality of an organism over [1]time. Cellular senescence is defined as a stress response by which cultured cells irreversibly lose their proliferative capacity, which leads to organismal [2]aging. However, since cellular senescence studies are performed using cell cultures in vitro and most mammalian cells are non-proliferative, the impact of senescence on aging is controversial. Moreover, recent studies suggest a proliferation-independent senescence-like process in post-mitotic cells, termed as amitosenescence, which might be involved in organismal [3]aging. [4]

Researchers in the field have suggested a number of theories to explain the causes and mechanisms of the aging process. Schmeer and colleagues have proposed four key points that have been extracted from the theories on [5]aging:

  1. The stochastic causative approach propagates that aging is a consequence of the stochastic events of the different hallmarks of aging.
  2. 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.
  3. The programmed causative approach states that aging is programmed (at least [6]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 [7](SASP). The effects of this control mechanism are attenuated by anti-aging factors like Sirtuin 1 and Forkhead box protein [9]O.
  4. 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.
  5. 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 [8]age.

In your opinion, which theory of aging completely explains all the complex processes that occur in cells and organs relating to why we grow old?


[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

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