Strategies for engineered negligible senescence

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Strategies for engineered negligible senescence (SENS) is a range of proposed regenerative medical therapies, either planned or currently in development, for the periodic repair of all age-related damage to human tissue. These therapies have the ultimate aim of maintaining a state of negligible senescence in patients and postponing age-associated disease. [1] SENS was first defined by British biogerontologist Aubrey de Grey. Many mainstream scientists believe that it is a fringe theory. [2] De Grey later highlighted similarities and differences of SENS to subsequent categorization systems of the biology of aging, such as the highly influential Hallmarks of Aging published in 2013. [3] [4]

Contents

While some biogerontologists support the SENS program, others contend that the ultimate goals of de Grey's programme are too speculative given the current state of technology. [5] [6] The 31-member Research Advisory Board of de Grey's SENS Research Foundation have signed an endorsement of the plausibility of the SENS approach. [7]

Framework

The arrows with flat heads are a notation meaning "inhibits", used in the literature of gene expression and gene regulation. Aging treatment approaches.jpg
The arrows with flat heads are a notation meaning "inhibits", used in the literature of gene expression and gene regulation.

The term "negligible senescence" was first used in the early 1990s by professor Caleb Finch to describe organisms such as lobsters and hydras, which do not show symptoms of aging. The term "engineered negligible senescence" first appeared in print in Aubrey de Grey's 1999 book The Mitochondrial Free Radical Theory of Aging. [8] De Grey defined SENS as a "goal-directed rather than curiosity-driven" [9] approach to the science of aging, and "an effort to expand regenerative medicine into the territory of aging". [10]

The ultimate objective of SENS is the eventual elimination of age-related diseases and infirmity by repeatedly reducing the state of senescence in the organism. The SENS project consists in implementing a series of periodic medical interventions designed to repair, prevent or render irrelevant all the types of molecular and cellular damage that cause age-related pathology and degeneration, in order to avoid debilitation and death from age-related causes. [1]

Strategies

As described by SENS, the following table details major ailments and the program's proposed preventative strategies: [11]

IssueProposed countermeasures
Extracellular aggregates Immunotherapeutic clearance
Accumulation of senescent cells Senescence marker-targeted toxins, immunotherapy
Extracellular matrix stiffeningAGE-breaking molecules, tissue engineering
Intracellular aggregatesNovel lysosomal hydrolases
Mitochondrial mutations Allotopic expression of 13 proteins
Cancerous cellsRemoval of telomere-lengthening machinery
Cell loss, tissue atrophyStem cells and tissue engineering

Scientific reception

While some fields mentioned as branches of SENS are supported by the medical research community, e.g., stem cell research, anti-Alzheimers research and oncogenomics, the SENS programme as a whole has been a highly controversial proposal. Many of its critics argued in 2005 that the SENS agenda was fanciful and that the complicated biomedical phenomena involved in aging contain too many unknowns for SENS to be fully implementable in the foreseeable future. [12]

Cancer may deserve special attention as an aging-associated disease, but the SENS claim that nuclear DNA damage only matters for aging because of cancer has been challenged in other literature, [13] as well as by material studying the DNA damage theory of aging. More recently, biogerontologist Marios Kyriazis has criticised the clinical applicability of SENS [14] [15] by claiming that such therapies, even if developed in the laboratory, would be practically unusable by the general public. [16] De Grey responded to one such criticism.[ further explanation needed ] [17]

2005 EMBO Reports statement

In November 2005, 28 biogerontologists published a statement of criticism in EMBO Reports , "Science fact and the SENS agenda: what can we reasonably expect from ageing research?," [12] arguing "each one of the specific proposals that comprise the SENS agenda is, at our present stage of ignorance, exceptionally optimistic," [12] and that some of the specific proposals "will take decades of hard work [to be medically integrated], if [they] ever prove to be useful." [12] The researchers argue that while there is "a rationale for thinking that we might eventually learn how to postpone human illnesses to an important degree," [12] increased basic research, rather than the goal-directed approach of SENS, is currently the scientifically appropriate goal.

Technology Review contest

In February 2005, the MIT Technology Review published an article by Sherwin Nuland, a Clinical Professor of Surgery at Yale University and the author of "How We Die", [18] that drew a skeptical portrait of SENS, at the time de Grey was a computer associate in the Flybase Facility of the Department of Genetics at the University of Cambridge. [19] While Nuland praised de Grey's intellect and rhetoric, he criticized the SENS framework both for oversimplifying "enormously complex biological problems" and for promising relatively near-at-hand solutions to those unsolved problems. [19]

During June 2005, David Gobel, CEO and co-founder of the Methuselah Foundation with de Grey, offered Technology Review $20,000 to fund a prize competition to publicly clarify the viability of the SENS approach. In July 2005, Jason Pontin announced a $20,000 prize, funded 50/50 by Methuselah Foundation and MIT Technology Review. The contest was open to any molecular biologist, with a record of publication in biogerontology, who could prove that the alleged benefits of SENS were "so wrong that it is unworthy of learned debate." [20] Technology Review received five submissions to its challenge. In March 2006, Technology Review announced that it had chosen a panel of judges for the Challenge: Rodney Brooks, Anita Goel, Nathan Myhrvold, Vikram Sheel Kumar, and Craig Venter. [21] Three of the five submissions met the terms of the prize competition. They were published by Technology Review on June 9, 2006. On July 11, 2006, Technology Review published the results of the SENS Challenge. [22]

In the end, no one won the $20,000 prize. The judges felt that no submission met the criterion of the challenge and discredited SENS, although they unanimously agreed that one submission, by Preston Estep and his colleagues, was the most eloquent. Craig Venter succinctly expressed the prevailing opinion: "Estep et al. ... have not demonstrated that SENS is unworthy of discussion, but the proponents of SENS have not made a compelling case for it." [22] Summarizing the judges' deliberations, Pontin wrote in 2006 that SENS is "highly speculative" and that many of its proposals could not be reproduced with current scientific technology. Myhrvold described SENS as belonging to a kind of "antechamber of science" where they wait until technology and scientific knowledge advance to the point where it can be tested. [22] [23] Estep and his coauthors challenged the result of the contest by saying both that the judges had ruled "outside their area of expertise" and had failed to consider de Grey's frequent misrepresentations of the scientific literature. [24]

SENS Research Foundation

The SENS Research Foundation is a non-profit organization co-founded by Michael Kope, Aubrey de Grey, Jeff Hall, Sarah Marr and Kevin Perrott, which is based in California, United States. Its activities include SENS-based research programs and public relations work for the acceptance of and interest in related research.

See also

Related Research Articles

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. The word senescence can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

Fringe science refers to ideas whose attributes include being highly speculative or relying on premises already refuted. Fringe science theories are often advanced by persons who have no traditional academic science background, or by researchers outside the mainstream discipline. The general public has difficulty distinguishing between science and its imitators, and in some cases a "yearning to believe or a generalized suspicion of experts is a very potent incentive to accepting pseudoscientific claims".

<span class="mw-page-title-main">Aubrey de Grey</span> English author and biogerontologist

Aubrey David Nicholas Jasper de Grey is an English biomedical gerontologist. He is the author of The Mitochondrial Free Radical Theory of Aging (1999) and co-author of Ending Aging (2007). De Grey is known for his view that medical technology may enable human beings alive today not to die from age-related causes. As an amateur mathematician, he has contributed to the study of the Hadwiger–Nelson problem in geometric graph theory, making the first progress on the problem in over 60 years.

<span class="mw-page-title-main">Biogerontology</span> Sub-field of gerontology

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick has said that the natural average lifespan for a human is around 92 years and, if humans do not invent new approaches to treat aging, they will be stuck with this lifespan. James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000. Many surveyed biogerontologists have predicted life expectancies of more than three centuries for people born after the year 2100. Other scientists, more controversially, suggest the possibility of unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age". The idea of this approach is to use presently available technology to extend lifespans of currently living humans long enough for future technological progress to resolve any remaining aging-related issues. This concept has been referred to as longevity escape velocity.

Rejuvenation is a medical discipline focused on the practical reversal of the aging process.

Gregory M. Fahy is a California-based cryobiologist, biogerontologist, and businessman. He is Vice President and Chief Scientific Officer at Twenty-First Century Medicine, Inc, and has co-founded Intervene Immune, a company developing clinical methods to reverse immune system aging. He is the 2022–2023 president of the Society for Cryobiology.

Following is a list of topics related to life extension:

<i>Rejuvenation Research</i> Academic journal

Rejuvenation Research is a bimonthly peer-reviewed scientific journal published by Mary Ann Liebert that covers research on rejuvenation and biogerontology. The journal was established in 1998. The current acting editor-in-chief is Ben Zealley. It is the official journal of the European Society of Preventive, Regenerative and Anti-Aging Medicine as well as PYRAMED: World Federation and World Institute of Preventive & Regenerative Medicine.

The following outline is provided as an overview of and topical guide to life extension:

<span class="mw-page-title-main">Preston Estep</span> Biogerontologist

Preston "Pete" Wayne Estep III is an American biologist and science and technology advocate. He is a graduate of Cornell University, where he did neuroscience research, and he earned a Ph.D. in Genetics from Harvard University. He did his doctoral research in the laboratory of genomics pioneer Professor George M. Church at Harvard Medical School.

<span class="mw-page-title-main">Aging-associated diseases</span> Type of disease

An aging-associated disease is a disease that is most often seen with increasing frequency with increasing senescence. They are essentially complications of senescence, distinguished from the aging process itself because all adult animals age but not all adult animals experience all age-associated diseases. The term does not refer to age-specific diseases, such as the childhood diseases chicken pox and measles, only diseases of the elderly. They are also not accelerated aging diseases, all of which are genetic disorders.

<span class="mw-page-title-main">Longevity escape velocity</span> Hypothetical situation in which life expectancy is extended longer than the time that is passing

In the life extension movement, longevity escape velocity (LEV), actuarial escape velocity or biological escape velocity is a hypothetical situation in which one's remaining life expectancy is extended longer than the time that is passing. For example, in a given year in which longevity escape velocity would be maintained, medical advances would increase people's remaining life expectancy more than the year that just went by. The term is meant as an analogy to the concept of escape velocity in physics, which is the minimum speed required for an object to indefinitely move away from a gravitational body despite the gravitational force pulling the object towards the body.

<span class="mw-page-title-main">Methuselah Foundation</span> U.S. nonprofit organization

The Methuselah Foundation is an American-based global non-profit organization based in Springfield, Virginia, with a declared mission to "make 90 the new 50 by 2030" by supporting tissue engineering and regenerative medicine therapies. The organization was originally incorporated by David Gobel in 2001 as the Performance Prize Society, a name inspired by the British governments Longitude Act, which offered monetary rewards for anyone who could devise a portable, practical solution for determining a ship's longitude.

<i>Ending Aging</i> 2007 book by Aubrey de Grey and Michael Rae

Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime is a 2007 book written by biogerontologist Aubrey de Grey, with his research assistant Michael Rae. Ending Aging describes de Grey's proposal for eliminating aging as a cause of debilitation and death in humans, and restoring the body to an indefinitely youthful state, a project that he calls the "strategies for engineered negligible senescence" ("SENS"). De Grey argues that defeating aging is feasible, possibly within a few decades, and he outlines steps that can be taken to hasten the development of regenerative medicine treatments for each side of aging.

Pro-aging trance, also known as pro-aging edifice, is a term coined by British author and biomedical gerontologist Aubrey de Grey to describe the broadly positive and fatalistic attitude toward aging in society.

The SENS Research Foundation is a non-profit organization that does research programs and public relations work for the application of regenerative medicine to aging. It was founded in 2009, located in Mountain View, California, USA. The organization publishes its reports annually.

<span class="mw-page-title-main">Negligible senescence</span> Organisms that do not exhibit evidence of biological aging

Negligible senescence is a term coined by biogerontologist Caleb Finch to denote organisms that do not exhibit evidence of biological aging (senescence), such as measurable reductions in their reproductive capability, measurable functional decline, or rising death rates with age. There are many species where scientists have seen no increase in mortality after maturity. This may mean that the lifespan of the organism is so long that researchers' subjects have not yet lived up to the time when a measure of the species' longevity can be made. Turtles, for example, were once thought to lack senescence, but more extensive observations have found evidence of decreasing fitness with age.

The anti-aging movement is a social movement devoted to eliminating or reversing aging, or reducing the effects of it. A substantial portion of the attention of the movement is on the possibilities for life extension, but there is also interest in techniques such as cosmetic surgery which ameliorate the effects of aging rather than delay or defeat it.

This timeline lists notable events in the history of research into senescence or biological aging, including the research and development of life extension methods, brain aging delay methods and rejuvenation.

References

  1. 1 2 de Grey, Aubrey; Rae, Michael (September 2007). Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime. New York, NY: St. Martin's Press, 416 pp. ISBN   0-312-36706-6.
  2. ↑ Warner, H.; Anderson, J.; Austad, S.; Bergamini, E.; Bredesen, D.; Butler, R.; Carnes, B. A.; Clark, B. F. C.; Cristofalo, V.; Faulkner, J.; Guarente, L.; Harrison, D. E.; Kirkwood, T.; Lithgow, G.; Martin, G.; Masoro, E.; Melov, S.; Miller, R. A.; Olshansky, S. J.; Partridge, L.; Pereira-Smith, O.; Perls, T.; Richardson, A.; Smith, J.; Von Zglinicki, T.; Wang, E.; Wei, J. Y.; Williams, T. F. (Nov 2005). "Science fact and the SENS agenda. What can we reasonably expect from ageing research?". EMBO Reports. 6 (11): 1006–1008. doi:10.1038/sj.embor.7400555. ISSN   1469-221X. PMC   1371037 . PMID   16264422.
  3. ↑ De Grey, Aubrey D.N.J. (2023). "The Divide-and-Conquer Approach to Delaying Age-Related Functional Decline: Where Are We Now?". Rejuvenation Research. 26 (6): 217–220. doi:10.1089/rej.2023.0057. PMID   37950714. S2CID   265127778.
  4. ↑ https://www.cell.com/fulltext/S0092-8674(13)00645-4
  5. ↑ Warner H; Anderson J; Austad S; et al. (November 2005). "Science fact and the SENS agenda. What can we reasonably expect from ageing research?". EMBO Reports. 6 (11): 1006–8. doi:10.1038/sj.embor.7400555. PMC   1371037 . PMID   16264422.
  6. ↑ Holliday R (April 2009). "The extreme arrogance of anti-aging medicine". Biogerontology. 10 (2): 223–8. doi:10.1007/s10522-008-9170-6. PMID   18726707. S2CID   764136.
  7. ↑ "Research Advisory Board". sens.org. Archived from the original on 14 June 2021. Retrieved 15 July 2021.
  8. ↑ de Grey, Aubrey (November 2003). The Mitochondrial Free Radical Theory of Aging. Austin, Texas: Landes Bioscience. ISBN   1-58706-155-4.
  9. ↑ Bulkes, Nyssa (March 6, 2006). "Anti-aging research breakthroughs may add up to 25 years to life Archived 2020-04-02 at the Wayback Machine ". The Northern Star. Northern Illinois University (DeKalb, USA).
  10. ↑ . "Age-Related Diseases: Medicine's Final Adversary?". Huffington Post Healthy Living.
  11. ↑ "Intro to SENS Research". SENS Research Foundation. Retrieved 2020-08-18.
  12. 1 2 3 4 5 Warner; et al. (2005). "Science fact and the SENS agenda. What can we reasonably expect from ageing research?". EMBO Reports. 6 (11): 1006–1008. doi:10.1038/sj.embor.7400555. PMC   1371037 . PMID   16264422.
  13. ↑ Best, BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. CiteSeerX   10.1.1.318.738 . doi:10.1089/rej.2009.0847. PMID   19594328.
  14. ↑ Kyriazis M (2014). "The impracticality of biomedical rejuvenation therapies: translational and pharmacological barriers". Rejuvenation Research. 17 (4): 390–6. doi:10.1089/rej.2014.1588. PMC   4142774 . PMID   25072550.
  15. ↑ Kyriazis, Marios (2015). "Translating laboratory anti-aging biotechnology into applied clinical practice: Problems and obstacles". World Journal of Translational Medicine. 4 (2): 51–4. doi: 10.5528/wjtm.v4.i2.51 .
  16. ↑ Kyriazis M, Apostolides A (2015). "The Fallacy of the Longevity Elixir: Negligible Senescence May be Achieved, but Not by Using Something Physical". Current Aging Science. 8 (3): 227–34. doi:10.2174/1874609808666150702095803. PMID   26135528.
  17. ↑ de Grey AD (2014). "The practicality or otherwise of biomedical rejuvenation therapies: a response to Kyriazis". Rejuvenation Research. 17 (4): 397–400. doi:10.1089/rej.2014.1599. PMID   25072964.
  18. ↑ Nuland, Sherwin (1994). How We Die: Reflections on Life's Final Chapter. New York: Knopf Random House. ISBN   0-679-41461-4.
  19. 1 2 Nuland, Sherwin (1 February 2005). "Do You Want to Live Forever?". MIT Technology Review. Retrieved 28 April 2021.
  20. ↑ Pontin, Jason (July 28, 2005). "The SENS Challenge Archived 2012-03-16 at the Wayback Machine ". Technology Review.
  21. ↑ Pontin, Jason (March 14, 2006). "We've picked the judges for our biogerontology prize Archived 2012-03-16 at the Wayback Machine ". Technology Review.
  22. 1 2 3 Pontin, Jason (July 11, 2006). "Is Defeating Aging Only A Dream? Archived 2020-04-02 at the Wayback Machine ". Technology Review.
  23. ↑ Garreau, Joel (October 31, 2007). "Invincible Man". Washington Post.
  24. ↑ Estep, Preston W. (11 July 2006). "Preston Estep et al. Dissent". MIT Technology Review. Retrieved 28 April 2021.

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