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Which theory of aging best explains why we grow old?

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Darko Savic
Darko Savic Jul 26, 2020
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

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 time. Cellular senescence is defined as a stress response by which cultured cells irreversibly lose their proliferative capacity, which leads to organismal 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 aging.
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 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 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.
  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 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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Creative contributions

Entropy and hormesis

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Darko Savic
Darko Savic Dec 02, 2020
Here are a few thoughts I've been entertaining for a while:

According to the second law of thermodynamics, everything in the universe has a tendency to move from the state of order to the state of randomness as time passes (increasing entropy). Anything that is non-random is being held as such by the energy contained within it (chemical bonds). This energy is gradually being lost to the surroundings, which makes the non-random thing increasingly random with time. Given enough time, everything that can, will fall apart, spread out, and mix with the surroundings to the point of chemical equilibrium - a final state where there is no more energy for anything to happen.

Stopping or reversing this process and creating anything non-random requires additional energy.

Life as we know it is specifically designed to work against this process. Living cells have countless molecular systems that are working round the clock to keep the organism as far away from the state of chemical equilibrium as possible. The only way for the cells to keep on living is to work against entropy.

Why hormesis seems to slow the process of aging

Entropy increases very slowly but surely. This is purely speculation on my end but I think one of the root causes of aging is the fact that entropy is too slow to be detected and thus efficiently countered by our adaptive, compensatory (anti-entropy) mechanisms. When the damage builds up and the protective mechanisms are eventually activated it might be too little, too late. Entropy also gradually but surely destroys the protective mechanisms.

Disruption of homeostasis via cold, heat, starvation, radiation, or any other harmful condition activates the organism’s adaptive, compensatory mechanisms. Hormesis is the process of stimulating these protective mechanisms via “low dose” disruption of homeostasis. The protective mechanisms use energy to keep the organism from reaching chemical equilibrium - which also holds entropy at bay. This is why hormesis (for example via caloric restriction) seems to be effective at slowing down the effects of aging.
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Only two theories

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Dragan Otasevic
Dragan Otasevic Sep 30, 2020
In this tweet Blagosklony says that there are only 2 theories:

  1. Hyperfunction theory of quasi-programmed aging.
  2. 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 Theory

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Mohammad Shazaib
Mohammad Shazaib Sep 30, 2020
Many theories have been proposed to describe the process of aging, but neither of these seems to be completely satisfactory. The conventional aging theories hold that aging isn't a version or programmed. Modern biological theories of aging in humans fall into two main classes: programmed and harm or error theories. The programmed theories imply that aging carries a biological timetable, perhaps a continuation of the one that governs youth growth and development. This law would depend on changes in gene expression that affect the systems responsible for maintenance, repair, and defense responses. The damage or mistake theories highlight environmental assaults to living organisms which cause cumulative damage at different levels as the reason for aging.

The programmed theory has three sub-categories:
  1. 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).
  2. 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).
  3. 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).
  4. 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).

Overall, while multiple theories of aging have been proposed, currently there is no consensus on this issue. Many of the proposed theories interact with each other in a complex way. By understanding and testing the existing and new aging theories, it may be possible to promote successful aging as well as to enhance the lifespan of mankind.




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