"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. It was later prefaced with the term "strategies" in the article Time to Talk SENS: Critiquing the Immutability of Human Aging 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. 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.
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. 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. Although media sources have occasionally described SENS as "Cambridge-based", the SENS project is free-standing with no exclusive university affiliation.
The goal of the Strategies for Engineered Negligible Senescence (SENS) is the complete reversal of all age-related illnesses and indefinite extension of the healthy human lifespan. 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.
De Grey defines aging as "the set of accumulated side effects from metabolism that eventually kills us", and, more specifically, as follows: "a collection of cumulative changes to the molecular and cellular structure of an adult organism, which result in essential metabolic processes, but which also, once they progress far enough, increasingly disrupt metabolism, resulting in pathology and death." 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." His approach to biomedical gerontology ("anti-aging medicine") is thus distinctive because of its emphasis on rejuvenation rather than attempting to slow the aging process.
He identifies what he believes to be the seven biological causes of senescence. According to de Grey, the causes of aging in humans are cell loss or atrophy (without replacement), oncogenic nuclear mutations and epimutations, cell senescence (Death-resistant cells), mitochondrial mutations, Intracellular junk or junk inside cells (lysosomal aggregates), extracellular junk or junk outside cells (extracellular aggregates), and random extracellular cross-linking.
For each of these problems, de Grey outlines possible solutions, with 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. He believes we will be able to apply these solutions before we completely understand the targeted aging mechanisms, which will take longer. He states 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.
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. He 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.
These are changes to the nuclear DNA (nDNA), the molecule that contains our genetic information, or to proteins which bind to the nDNA. Certain mutations can lead to cancer, and, according to de Grey, non-cancerous mutations and epimutations do not contribute to aging within a normal lifespan, so cancer is the only endpoint of these types of damage that must be addressed. 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, 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 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.
Mitochondria are components in our cells that are important for energy production. They contain their own genetic material, and mutations to their DNA can affect a cell’s ability to function properly. Indirectly, these mutations may accelerate many aspects of aging. 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. De Grey argues that experimental evidence demonstrates that the operation is feasible.
Our cells are constantly breaking down proteins and other molecules that are no longer useful or which can be harmful. Those molecules which can’t be digested simply accumulate as junk inside our cells. Atherosclerosis, macular degeneration and all kinds of neurodegenerative diseases (such as Alzheimer's disease) are associated with this problem. 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.
Harmful junk protein can also accumulate outside of our cells. The amyloid plaque seen in the brains of Alzheimer’s patients is one example. 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 identified as causes of many diseases most likely fit under this class.
Some of the cells in our bodies cannot be replaced, or can only be replaced very slowly—more slowly than they die. This decrease in cell number causes the heart to become weaker with age, and it also causes Parkinson's disease and impairs the immune system. 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. De Grey points out that this research involves a large number of details, and is already occurring on many fronts.
This is a phenomenon where the cells are no longer able to divide, but also do not die and let others divide. They may also do other things that they are not supposed to do, like secreting proteins that could be harmful. Immune senescence and type 2 diabetes are caused by this. Cells sometimes enter a state of resistance to signals that should cause 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.
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 and presbyopia. 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. 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.
SENS has been a highly controversial proposal, with many critics arguing that the SENS agenda is fanciful and the highly complicated biomedical phenomena involved in the aging process contain too many unknowns for SENS to be scientific or implementable in the foreseeable future.
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?," 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." 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 and a response from de Grey was published in the same November issue. De Grey summarizes these events in "The biogerontology research community's evolving view of SENS," published on the Methuselah Foundation website.
In February 2005, Technology Review, which is owned by the Massachusetts Institute of Technology, published an article by Sherwin Nuland, a Clinical Professor of Surgery at Yale University and the author of "How We Die", that drew a skeptical portrait of Aubrey de Grey, at the time a computer associate in the Flybase Facility of the Department of Genetics at the University of Cambridge. While admiring de Grey's intelligence, Nuland concluded that he "would surely destroy us in attempting to preserve us" because living for such long periods would undermine what it means to be human. In the same issue of the magazine, Jason Pontin, the editor in chief and publisher of Technology Review, criticised de Grey. Writing an editor's letter, titled Against Transcendence, he questioned the usefulness and appropriateness of introducing transcendentalism, or transhumanism, into science. The April 2005 issue of Technology Review contained a reply by Aubrey de Grey and numerous comments from readers.
In July 2005, Pontin announced a $20,000 prize open to any molecular biologist, with a record of publication in biogerontology, who could prove that SENS was "so wrong that it is unworthy of learned debate. Technology Review received five submissions to its Challenge. In March, of 2006, Technology Review announced that it had chosen a panel of judges for the Challenge. Three met the terms of the prize competition. They were published by Technology Review on June 9, 2006. Accompanying the three submissions were rebuttals by de Grey, and counter-responses to de Grey's rebuttals. On July 11, 2006, Technology Review published the results of the SENS Challenge.
In the end, no one won the $20,000 prize. The judges felt that no submission met the criterion of the challenge and disproved 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." Summarizing the judges' deliberations, Pontin wrote, "SENS is highly speculative. Many of its proposals have not been reproduced, nor could they be reproduced with today's scientific knowledge and technology. Echoing Myhrvold, we might charitably say that de Grey's proposals exist in a kind of antechamber of science, where they wait (possibly in vain) for independent verification. SENS does not compel the assent of many knowledgeable scientists; but neither is it demonstrably wrong." In a letter of dissent dated July 11, 2006 in Technology Review, Estep et al. criticized the ruling of the judges.
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."
There have been four SENS roundtables and three SENS conferences held. The first SENS roundtable was held in Oakland, California on October, 2000, and the last SENS roundtable was held in Bethesda, Maryland on July, 2004.
The three SENS Conferences were each held at Queens' College of the University of Cambridge in England. All the conferences were organized by 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 with the proceedings published in the Annals of the New York Academy of Sciences. The second SENS conference was held in September 2005 and was simply called Strategies for Engineered Negligible Senescence (SENS), Second Conference with the proceedings published in Rejuvenation Research. A third SENS conference was held in September, 2007, also at Queens' College of the University of Cambridge in England and organized by de Grey.
The Methuselah Foundation is a non-profit 501(c)(3) volunteer organization co-founded by Aubrey de Grey and David Gobel, which is based in Springfield, Virginia, United States. A major activity of the Methuselah Foundation is the Methuselah Mouse Prize, a prize designed to hasten the research into effective life extension interventions by awarding monetary prizes to researchers who stretch the lifespan of mice to unprecedented lengths. It's other interests include PR work for the acceptance of and interest in scientific anti-aging research and SENS-based research programs, all of which the foundation hopes will lead to a proposed Institute of Biomedical Gerontology.
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