Strategies for Engineered Negligible Senescence

Strategies for Engineered Negligible Senescence ( SENS ) is the term coined by British biogerontologist Aubrey of Gray for the diverse range of regenerative medical therapies, either planned or currently in development, [1] for the periodical repair of all age-related damage to human tissue with the ultimate purpose of maintaining a negligible senescence in the patient, thereby aiding postponing age-associated disease for as long as the therapies are reapplied. [2]

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 Aubrey’s Gray’s 1999 book The Mitochondrial Free Radical Theory of Aging , [3] and was later prefaced with the term “strategies” in the article Time to Talk SENS: Critiquing the Immunity of Human Aging [4] From Gray called SENS to “goal-directed rather than curiosity-driven” [5]approach to the science of aging, and “an effort to expand regenerative medicine into the territory of aging”. [6] To this end, SENS has identified seven categories of aging and a specific regenerative medical proposal for treatment.

While many biogerontologists find it “worthy of discussion” [7] [8] and SENS conferences feature important research in the field, [9] [10] some contend that the ultimate goals of Gray’s program are too speculative of the current state of technology, referring to it as “fantasy rather than science”. [11] [12]

Framework

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

The ultimate objective of SENS is the eventual elimination of age-related diseases and the state of senescence in the organism. The SENS project consists of implementing a series of periodic medical interventions designed to repair, prevent or render irrelevant all types of molecular and cellular damage that cause age-related pathology and degeneration, in order to prevent debilitation and death from age-related causes. [2]

From Gray, the term “accumulated side effects of metabolism that eventually kills us”, and more specifically, “a collection of cumulative changes to the molecular and cellularstructure of an adult organism , which result in essential metabolic processes, but which also, once they progress far enough, resulting in disrupt metabolism, resulting in pathologyand death. ” [13] He adds: ” geriatrics is the attempt to stop damage from Causing pathology; traditional gerontology is the attempt to stop metabolismfrom the cause of damage; and the SENS (engineering) approach is to eliminate the periodically, so that it is more important than any other cause of pathology. “The SENS approach to biomedical gerontology is thus distinctive because of its emphasis on tissue rejuvenation rather than attempting to slow the aging process.

By enumerating the various differences between young and old, identified by the science of biogerontology , a ‘damage’ report was drawn, which in turn formed the basis of the SENS strategy. The results of seven categories of ‘damage’, seven alterations to reversal would be negligible senescence :

  1. cell loss or atrophy (without replacement), [4] [13] [14]
  2. oncogenic nuclear mutations and epimutations , [15] [16] [17]
  3. cell senescence (Death-resistant cells), [18] [19]
  4. mitochondrial mutations, [20] [21]
  5. Intracellular junk or junk inside cells ( lysosomal aggregates), [22] [23]
  6. extracellular junk or junk outside cells (extracellular aggregates), [18] [19]
  7. random extracellular cross-linking. [18] [19]

SENS offers at least one strategy, with a research and a clinical component. The clinical component is required because of the proposed therapies, but not completely applied and approved for human trials. These strategies do not presuppose that the underlying metabolic mechanisms of aging are fully understood, only that they take precedence and are directly observable to science.

Types of aging damage and treatment schemes

Nuclear mutations / epimutations-OncoSENS

These are changes to the nuclear DNA ( nDNA ), or to proteins which bind to the nDNA. Certain mutations can lead to cancer .

This would need to be corrected in order to prevent or cure cancer . SENS focuses on a strategy called “whole-body prohibition of lengthening telomeres ” (WILT), which would be made possible by periodic regenerative medicinetreatments.

Mitochondrial mutations-MitoSENS

Mitochondria are components in our cells that are important for energy production. Because of the highly oxidative environment in mitochondria and Their Lack of the sophisticated repair systems, mitochondrial mutations are Believed to be a major issue of progressive cellular degeneration.

This would be corrected by allotopic expression -copying the DNA for mitochondria completely within the nucleus , where it is better protected. Gray argues that experimental evidence is feasible, however, that some mitochondrial proteins are too hydrophobic to survive from the cytoplasm to the mitochondria. [24]

Intracellular junk-LysoSENS

Our cells are Constantly breaking down proteins and other molecules That are no gold along Useful qui can be harmful. Those molecules which can not be digested in our cells, which are detected in the form of lipofuscin granules. Atherosclerosis , macular degeneration , liver spots and all kinds of neurodegenerative diseases (such as Alzheimer’s disease) are associated with this problem.

Junk inside cells may 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.

Extracellular junk-AmyloSENS

Harmful junk protein can accumulate outside of our cells. These cells are accumulated by a body, but they can not be digested or removed by its processes, such as the amyloid plaques characteristic of Alzheimer’s disease and other amyloidoses .

Junk outside cells may be removed by enhanced phagocytosis , and small drugs to break chemical beta-bonds. The large junk in this class can be removed surgically.

Cell loss and atrophy-RepleniSENS

Some of the cells in our bodies can not be replaced. This diminishes some of the most important tissues of the body. Muscle cells are lost in skeletal muscles and the heart, causing them to become frailer with age. Loss of neurons in the substantia nigra causes Parkinson’s disease , while loss of immune cells odd the immune system .

This can be corrected by therapies Partly Involving exercise and growth factors , purpose stem cell therapy , regenerative medicine and tissue engineering are required for Almost Certainly Any More than just partial replacement of lost cells.

Cell senescence-ApoptoSENS

Senescence is a phenomenon where the cells are no longer able to divide, but also do not die and let others divide. They may also have other harmful things, like secreting proteins. Degeneration of joints , immune senescence, accumulation of visceral fat and type 2 diabetes are caused by this. Cells sometimes enter a state of resistance to signals sent by a process called apoptosis , to instruct cells to destroy themselves.

Cells in this state could be eliminated by apoptosis (via suicide genes , vaccines , or recently discovered senolytic agents ), and healthy cells would be multiply to replace them.

Extracellular crosslinks-GlycoSENS

Cells are held together by special linking proteins. When too many cross-links form between cells in a tissue , the tissue can lose its elasticity and cause problems including arteriosclerosis, presbyopia and weakened skin texture. 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.

SENS proposed to further develop small-molecular drugs and enzymes to break links caused by sugar-bonding, known as advanced glycation endproducts , and other common forms of chemical linking.

Scientific controversy

While some fields have been broadly supported by the medical research community, eg stem cell research (RepleniSENS), anti-Alzheimers research (AmyloSENS) and oncogenomics (OncoSENS), the SENS program has been highly controversial. SENS is an agenda that is designed to be fully implemented in the future. Cancer may well deserve special attention as an aging-associated disease (OncoSENS), but the SENS claims that nuclear DNA damage only matters for cancer has been challenged in the literature [25]as well as by material in the product DNA damage theory of aging .

In November 2005, 28 biogenerologists published a statement of criticism in EMBO Reports , “Science Facts and Senses Agenda: What Can We Expect from Ageing Research ?,” [26] arguing “each one of the specific proposals that includes the SENS agenda is, at our present stage of ignorance, exceptionally optimistic, ” [26] and that some of the specific proposals will be made to work hard, [if] ever prove to be useful.” [26] 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,” [26]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 article by EMBO Reports previously published by de Gray [27] and a response from Gray was published in the same November issue. [28] De Gray summarizes these events in “The biogerontology research community’s evolving view of SENS,” published on the Methuselah Foundation website. [29]

In 2012, Colin Blakemore criticized Aubrey of Gray, but not SENS specifically, in a debate hosted by the Oxford University Scientific Society. quote needed ]

More recently, biogerontologist Marios Kyriazis has sharply criticized the clinical applicability of SENS [30] [31] claiming that such therapies, even if developed in the laboratory, would be practically unusable by the general public. [32]De Gray responded to such criticism. [33]

Technology Review controversy

In February 2005, Technology Review , which is owned by the Massachusetts Institute of Technology , published by Sherwin Nuland , a Clinical Professor of Surgery at Yale University and the author of “How We Die,” [34] that drew a skeptical portrait SENS, at the time of Gray was a computer associate in the Flybase Facility of the Department of Genetics at the University of Cambridge . The April 2005 issue of Technology Review is a reply by Aubrey of Gray [35] and comments from readers. [36]

During June 2005, David Gobel , CEO and co-founder of the Methuselah Foundation offered $ 20,000 of technology to the viability of the SENS approach. In July 2005, Pontin announced a $ 20,000 prize, funded 50/50 by Methuselah Foundation and MIT Technology Review, to any molecular biologist, with a record of publication in biogerontology, which could prove that the consequences of SENS were “so wrong that it is unworthy of learned debate. ” [37] Technology Review received five submissions to its Challenge. In March 2006, Technology Review announced that it was chosen by the panel of judges for the Challenge: Rodney Brooks , Anita Goel ,Nathan Myhrvold , Vikram Sheel Kumar , and Craig Venter . [38] Three of the five submissions put the terms of the prize competition. They were published by Technology Review on June 9, 2006. Accompanying the three submissions were rebuttals by Gray, and counter-responses to Gray’s rebuttals. On July 11, 2006, Technology Review published the results of the SENS Challenge. [7] [39]

In the end, no one won the $ 20,000 prize. The judges felt that no submission met the criteria of the challenge and discredited SENS, 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 shown that SENS is unworthy of discussion, but the proponents of SENS have not made a compelling case for it.” [7] Summarizing the judges’ deliberations, Pontin wrote that SENS is “highly speculative” and that many of its proposals could not be reproduced with the scientific technology of that period. clarification needed ]Myhrvold described SENS as belonging to a kind of “antechamber of science” where they can not be tested. [7] [8] In a letter of dissent dated July 11, 2006 in Technology Review, Estep et al. criticized the ruling of the judges.

Social and economic implications

Of the roughly 150,000 people who die each day across the globe, about two thirds-100,000 per day-of-age-related causes. [40] In industrialized nations, the proportion is much higher, reaching 90%. [40]

De Gray and Other Scientists in the General Field of the United States argue that the costs of an increase in the cost of living will increase. Olshansky et al. 2006 argues, for example, that the total cost of Alzheimer’s disease in the US alone will increase from $ 80-100 billion today to more than $ 1 trillion in 2050. [41] “Take a closer look at 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 as a result of the disease in the United States will have more than 16 million people in the world Globally, AD prevalence The US economic toll is currently $ 80- $ 100 billion, but by 2050 more than $ 1 trillion will be spent annually on AD and related The impact of this single disease will be catastrophic, and this is just one example. “[41]

SENS meetings

There are four SENS roundtables and six SENS conferences held. [42] [43] The first SENS roundtable was held in Oakland, California on October, 2000, [44] and the last roundtable SENS was held in Bethesda, Maryland on July, 2004. [45]

On March 30-31, 2007 at North American SENS Symposium was held in Edmonton, Alberta , Canada as the Edmonton Aging Symposium . [46] [47] Another SENS-related conference (“Understanding Aging”) was held at UCLA in Los Angeles , California on June 27-29, 2008 [48]

Six SENS conferences have been held at Queens College, Cambridge in England . All the conferences were organized by de Gray 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 [49] with the proceedings published in the Annals of the New York Academy of Sciences . [50]
  • The second SENS conference was held in September 2005 and was simply called Strategies for Engineered Negligible Senescence (SENS), Second Conference [51] with the proceedings published in Rejuvenation Research .
  • The third SENS conference was held in September, 2007. [52]
  • The fourth SENS conference was held September 3-7, 2009.
  • The fifth was held August 31 – September 4, 2011, like the first four, it was at Queens College, Cambridge in England, organized by Gray. [53] [54] Videos of the presentations are available .
  • The sixth SENS conference (SENS6) was held from September 3-7, 2013.

Another meeting was held in August 2014 in Santa Clara, California. [43]

SENS Research Foundation

Main article: SENS Research Foundation

The SENS Research Foundation is a non-profit organization co-founded by Michael Kope, Aubrey Gray , Jeff Hall, Sarah Marr and Kevin Perrott, who 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.

Before March 2009, the SENS research program was mainly pursued by the Methuselah Foundation , co-founded by Aubrey of Gray and David Gobel. The Methuselah Foundation is most notable for establishing the Methuselah Mouse Prize , a monetary prize awarded to the length of time spent. [55]

For 2013, The SENS Research Foundation has a research budget of approximately $ 4 million annually, from a personal contribution of $ 13 million from Aubrey of Gray’s [56] own wealth, and the other half from external donors, with the largest external donor being Peter Thiel , and another Internet entrepreneur Jason Hope, [57] has recently begun to contribute comparable sums.

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