Engineered negligible senescence

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Engineered negligible senescence refers to an engineered prevention or reversal of cellular aging (referred to as senescence in biology).

The expression was coined by British biogerontologist Aubrey de Grey and first appeared in print in his 1999 book The Mitochondrial Free Radical Theory of Aging.[1] It was later prefaced with the term 'strategies' in the article 'Time to Talk SENS: Critiquing the Immutability of Human Aging'[2] and is used in the context of de Grey's life extension medical proposal, Strategies for Engineered Negligible Senescence (SENS). De Grey argues for a "goal-directed rather than curiosity-driven" approach to the science of aging, and to this purpose he identifies what he believes are the seven causes of aging and their potential methods of treatments. De Grey in this sense views medicine as a branch of engineering.[3] He believes the next great social debate will occur when aging research progresses to the point that public funds could be used to accelerate the arrival of effective treatment for aging.[4]

The proposal has received widespread media attention, including from the BBC, the New York Times, and 60 Minutes, though it has been questioned by mainstream biologists[5]. Dr. de Grey has summarized the entire SENS program in his 2007 book Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime[6]. Although media sources have occasionally described SENS as "Cambridge-based"[7], the SENS project is free-standing with no exclusive university affiliation.[8]

Contents

[edit] Proposal

[edit] Overview

The arrows with flat heads are a notation meaning 'inhibits,' used in the literature of gene expression and gene regulation.
The arrows with flat heads are a notation meaning 'inhibits,' used in the literature of gene expression and gene regulation.

As de Grey states, "geriatrics is the attempt to stop damage from causing pathology; traditional gerontology is the attempt to stop metabolism from causing damage; and the SENS (engineering) approach is to eliminate the damage periodically, so keeping its abundance below the level that causes any pathology."[9] De Grey's approach to biomedical gerontology ("anti-aging medicine") is thus distinctive because of its emphasis on rejuvenation rather than attempting to slow the aging process.

De Grey has published papers in this area in prominent journals with some of biogerontology's foremost researchers, including Bruce Ames, Leonid Gavrilov, and S. Jay Olshansky, as well as other thinkers such as Gregory Stock.[10] De Grey has also received support from other prominent scientists, such as William Haseltine, the biotech pioneer of Human Genome Sciences, who in March 2005 stated regarding the Methuselah Mouse Prize (see section below), "there’s nothing to compare with this effort, and it has already contributed significantly to the awareness that regenerative medicine is a near term reality, not an if." [11]

De Grey proposes that engineered negligible senescence therapies could extend the human lifetime by many centuries or millennia, as early therapies give them enough time to seek more effective therapies later on. De Grey describes an actuarial escape velocity of life extension, when advances in senescence treatment come rapidly enough to save the lives of the oldest beneficiaries of the previous treatments.[12]

De Grey and other scientists in the general field have argued that the costs of a rapidly growing aging population will increase to the degree that the costs of an accelerated pace of aging research are easy to justify in terms of future costs avoided. Olshansky et al. 2006 argue, for example, that the total economic cost of Alzheimer's disease in the US alone will increase from $80-100 billion today to more than $1 trillion in 2050. "Consider what is likely to happen if we don't [invest further in aging research]. Take, for instance, the impact of just one age-related disorder, Alzheimer disease (AD). For no other reason than the inevitable shifting demographics, the number of Americans stricken with AD will rise from 4 million today to as many as 16 million by midcentury. This means that more people in the United States will have AD by 2050 than the entire current population of the Netherlands. Globally, AD prevalence is expected to rise to 45 million by 2050, with three of every four patients with AD living in a developing nation. The US economic toll is currently $80-$100 billion, but by 2050 more than $1 trillion will be spent annually on AD and related dementias. The impact of this single disease will be catastrophic, and this is just one example."[13]

[edit] The seven causes of aging

De Grey defines aging as "the set of accumulated side effects from metabolism that eventually kills us", and his proposal identifies what he believes to be the seven biological causes of senescence and outlines possible solutions, each with both a research and a clinical component. The clinical component is required because in some of the proposed therapies, feasibility has already been proven, but not completely applied and approved for use by human beings. De Grey believes we will be able to apply these solutions before we completely understand the targeted aging mechanisms, which will take longer.[14][15]

De Grey claims that the goals work together to eliminate known causes of human senescence, are concrete, seem achievable, and are considered feasible by experts in the applicable fields. The goals were said to be taken from classical literature describing the biological causes of senescence.

  1. Cell loss or atrophy[16] Cell depletion can be partly corrected by therapies involving exercise and growth factors. But stem cell therapy is almost certainly required for any more than just partial replacement of lost cells. Dr. de Grey points out that this research involves a large number of details, and is already occurring on many fronts.
  2. Nuclear mutations and epimutations[17][18][19][20] A mutation in a functional gene of a cell can cause that cell to malfunction or to produce a malfunctioning product, because of the sheer number of cells Dr. de Grey believes that redundancy takes care of this problem although cells that have mutated to produce toxic products might have to be disabled. In Dr. de Grey's opinion, the effect of mutations and epimutations that really matters is cancer, this is because if even one cell turns into a cancer cell it might spread and become deadly. This would need to be corrected by whole-body interdiction of lengthening telomeres, or any other cure for cancer, if any is ever found.
  3. Mutant mitochondria[21] Because of the highly oxidative environment in mitochondria and their lack of the sophisticated repair systems found in cell nucleus, mitochondrial mutations are believed to a be a major cause of progressive cellular degeneration. This would be corrected by moving the DNA for mitochondria completely within the cellular nucleus, where it is better protected. In humans, all but 13 proteins are already protected in this way. Dr. de Grey claims that experimental evidence demonstrates that the operation is feasible.
  4. Death-resistant cells[22] Cells sometimes enter a state of resistance to signals that should causes them to destroy themselves, a process called apoptosis; an example is the state known as cellular senescence. These cells could be eliminated might be corrected by forcing such cells to apoptose. Cell killing with suicide genes or vaccines is suggested for making the cells undertake apoptosis. Healthy cells would multiply to replace them.
  5. Extracellular cross-links[23][24][25]These are chemical bonds between structures that are part of the body, but not within a cell. In senescent people many of these become brittle and weak. Dr. de Grey proposes to further develop small-molecular drugs and enzymes to break links caused by sugar-bonding (glycation), and other common forms of chemical linking.
  6. Junk outside cells[26] Junk outside cells might be removed by enhanced phagocytosis (the normal process used by the immune system), and small drugs able to break chemical beta-bonds. The large junk in this class can be removed surgically. Junk here means useless things accumulated by a body, but which cannot be digested or removed by its processes, such as the amyloid plaques characteristic of Alzheimer's disease. The oft-mentioned 'toxins' that are claimed to cause many diseases most likely fits under this class.
  7. Junk inside cells[27][28] Junk inside cells might be removed by adding new enzymes to the cell's natural digestion organ, the lysosome. These enzymes would be taken from bacteria, molds and other organisms that are known to completely digest animal bodies.

[edit] Major donors

Peter Thiel, co-founder of PayPal, pledged $3.5 Million to the Methuselah Foundation for SENS research. Justin Bonomo, professional poker player, has pledged 5% of his tournament winnings for SENS research. Kevin Dewalt has pledged $10 for every video response he gets to Kevin's End Aging Challenge on youtube.

[edit] Methuselah Mouse Prize

Main article: Methuselah Mouse Prize

In 2003, de Grey co-founded (with David Gobel) the Methuselah Mouse Prize, a prize designed to accelerate research into effective life extension interventions by awarding monetary prizes to researchers who extend the lifespan of mice to unprecedented lengths. Regarding this, De Grey stated in March 2005, "if we are to bring about real regenerative therapies that will benefit not just future generations, but those of us who are alive today, we must encourage scientists to work on the problem of aging." The prize reached $3 million USD in November 2005, after having reached $1.5 million USD in August 2005. De Grey believes that once this objective has been achieved in mice, a large amount of funding will be diverted to this kind of research, which would accelerate progress.

[edit] Criticism

SENS has been a highly controversial proposal, with many critics arguing the highly complicated biomedical phenomena involved contain too many unknowns for intervention to be considered remotely foreseeable.

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?,"[29] arguing "each one of the specific proposals that comprise the SENS agenda is, at our present stage of ignorance, exceptionally optimistic," and that some of the specific proposals "will take decades of hard work [to be medically integrated], if [they] ever prove to be useful [which is not certain]."

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," increased basic research, rather than the goal-directed approach of SENS, is presently the scientifically appropriate goal.

This article was written in response to a July 2005 EMBO reports article previously published by de Grey[30] and a response from de Grey was published in the same November issue.[31] De Grey summarizes these events in "The biogerontology research community's evolving view of SENS," published on the SENS website.[32]

[edit] SENS meetings

There have been four SENS roundtables and three SENS conferences held. The first SENS roundtable was held in Oakland, California on October, 2000 [33] and the last SENS roundtable was held in Bethesda, Maryland on July, 2004[34].

There have been three SENS Conferences, each held at Queens' College of the University of Cambridge in England. All the conferences were organized by Aubrey de Grey and all featured world-class researchers in the field of biogerontology. The first SENS conference was held in September 2003 as the 10th Congress of the International Association of Biomedical Gerontology[35] with the proceedings published in the Annals of the New York Academy of Sciences[36]. The second SENS conference was held in September 2005 and was simply called Strategies for Engineered Negligible Senescence (SENS), Second Conference[37] with the proceedings published in Rejuvenation Research[38]. A third SENS conference was held in September, 2007, also at Queens' College of the University of Cambridge in England and organized by Aubrey de Grey[39].

On March 30-31, 2007 the first North American SENS conference was held in Edmonton, Alberta, Canada as the Edmonton Aging Symposium[40][41].

[edit] References

  1. ^ Austin, Texas: Landes Bioscience.
  2. ^ Annals of the New York Academy of Sciences, vol. 959 (2002), pp. 452-462.
  3. ^ star.niu.edu
  4. ^ star.niu.edu
  5. ^ The Quest for Immortality, 60 Minutes
  6. ^ (September 4, 2007) Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime. St. Martin's Press, 400. ISBN 0312367066. 
  7. ^ eg [http://news.bbc.co.uk/1/hi/uk/4003063.stm 'We will be able to live to 1,000', BBC News
  8. ^ SENS website
  9. ^ Strategies for Engineered Negligible Senescence (SENS). Retrieved on April 8, 2008.
  10. ^ Sherwin Nuland, Do You Want to Live Forever?, Technology Review
  11. ^ Britt, Robert Roy (March 9, 2005), “Anti-Aging Prize Tops $1 Million”, LiveScience, <http://www.livescience.com/health/050309_m_prize.html> 
  12. ^ Escape Velocity: Why the Prospect of Extreme Human Life Extension Matters Now, PLOS Biology, June 15, 2004
  13. ^ The Scientist : The Longevity Dividend
  14. ^ admin-sun1.gen.cam.ac.uk
  15. ^ aubrey_interview
  16. ^ Brody H. Organization of the cerebral cortex III. J Comp Neurol 1955; 102:511-556. PMID 14381544
  17. ^ Szilard L. On the nature of the ageing process. Proc Natl Acad Sci USA 1959; 45:35-45.
  18. ^ Cutler RG. The dysdifferentiation hypothesis of mammalian aging and longevity. In: The Aging Brain: Cellular and Molecular Mechanisms of Aging in the Nervous System (Gicobini E et al., eds), Raven (New York), 1982, pp. 1-19.
  19. ^ de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers. Annals NY Acad Sci 2004; 1019:147-170. PDF
  20. ^ de Grey ADNJ. Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention. Front Biosci 2005; 10:2420-2429. PDF
  21. ^ Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972;20:145-147.
  22. ^ Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614-636. PMID 14315085
  23. ^ Monnier VM, Cerami A. Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 1981;211:491-493. PMID 6779377
  24. ^ de Grey ADNJ. Challenging but essential targets for genuine anti-ageing drugs. Expert Opinion on Therapeutic Targets 2003; 37(1):1-5. PDF
  25. ^ de Grey ADNJ. Foreseeable pharmaceutical repair of age-related extracellular damage. Current Drug Targets, in press. PDF
  26. ^ Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und psychisch-gerichtliche Medizin, Berlin, 1907, 64: 146-148.
  27. ^ Strehler BL, Mark DD, Mildvan AS, Gee MV. Rate and magnitude of age pigment accumulation in the human myocardium. J Gerontol 1959; 14:430-439. PMID 13835175.
  28. ^ de Grey ADNJ, Alvarez PJJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases. Ageing Res Rev 2005; 4(3):315-338. PDF
  29. ^ Anderson et al., (2005) EMBO Reports 6(11):1006-8
  30. ^ Resistance to debate on how to postpone ageing is delaying progress and costing lives
  31. ^ Like it or not, life-extension research extends beyond biogerontology, EMBO Reports 6, S1, S49–S53]
  32. ^ The biogerontology research community's evolving view of SENS
  33. ^ SENS roundtable 1: Biotechnological foreseeability of ENS. Official SENS website. Aubrey de Grey (October 1, 2000). Retrieved on 2008-04-08.
  34. ^ SENS roundtable 4: Enhancing lysosomal catabolic function using microbial enzymes. Official SENS website. Aubrey de Grey (July 26, 2004). Retrieved on 2008-04-08.
  35. ^ The International Association of Biomedical Gerontology 10th Congress. Official SENS website. Aubrey de Grey (September 19-23, 2003). Retrieved on 2008-04-08.
  36. ^ Aubrey D. N. J. De Grey, Editor (June 2004). "Strategies for Engineered Negligible Senescence: Why Genuine Control of Aging May Be Foreseeable". 'Annals of the New York Academy of Sciences' 1019 (1). PMID 15247082. 
  37. ^ Strategies for Engineered Negligible Senescence (SENS), Second Conference. Official SENS website. Aubrey de Grey (September 7-11, 2005). Retrieved on 2008-04-08.
  38. ^ Aubrey de Grey, Editor (Fall/Winter 2006). "Strategies for Engineered Negligible Senescence". Rejuvenation Research 9 (3/4). doi:10.1089/rej.2006.9.429. PMID 17105378. 
  39. ^ Strategies for Engineered Negligible Senescence (SENS), Third Conference. Official SENS website. Aubrey de Grey (September 6-10, 2007). Retrieved on 2008-04-08.
  40. ^ Edmonton Aging Symposium Program (March 30-31, 2007). Retrieved on 2007-04-14.
  41. ^ Edmonton Aging Symposium online video/mp3/PowerPoint of presentations (March 30-31, 2007). Retrieved on 2007-04-14.
  • Olshansky, S. J., Perry, D., Miller, R. A., Butler, R. N. (2006). "The Longevity Dividend". The Scientist 20 (3): 28.

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