Strategies for engineered negligible senescence

Strategies for Engineered Negligible Senescence (SENS) is the term coined by British biogerontologist Aubrey de Grey for a diverse range of regenerative medical therapies currently in development, for the periodical repair of all age-related damage to human tissue, a technology which, he has argued, would maintain a state of negligible senescence in the patient, thereby postponing age-associated disease for as long as the therapies are reapplied.

The term "negligible senescence" was first used in 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, and was later prefaced with the term "strategies" in the article Time to Talk SENS: Critiquing the Immutability of Human Aging De Grey argues for a "goal-directed rather than curiosity-driven" approach to the science of aging, and to this purpose he tentatively identifies seven categories of "damages" a specific approach for treating each.

SENS has received media attention but has been criticized by some scientists. While many biogerontologists find it "worthy of discussion" and SENS conferences feature important research in the field, some contend that de Grey's programme is too speculative given current scientific research, referring to it as "fantasy rather than science".

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 infirmity by repeatedly reducing the state of senectitude 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.

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 is thus distinctive because of its emphasis on rejuvenation rather than attempting to slow the aging process.

By comparing the various respects in which aged and young tissue differ at a cellular level, a 'damage' report was drawn, which in turn forms the basis of the SENS strategy. The results fell into seven main categories of 'damage', seven alterations whose reversal would constitute negligible senescence:

1. cell loss or atrophy (without replacement),
2. oncogenic nuclear mutations and epimutations,
3. cell senescence (Death-resistant cells),
4. mitochondrial mutations,
5. Intracellular junk or junk inside cells (lysosomal aggregates),
6. extracellular junk or junk outside cells (extracellular aggregates),
7. 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.

Types of aging damage and treatment schemes

Cancer-causing nuclear mutations/epimutations—OncoSENS

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 a cure for cancer, if any is ever found. The SENS program focuses on a strategy called "whole-body interdiction of lengthening telomeres" (WILT), which would be made possible by periodic regenerative medicine treatments (see below). Restoring telomeres would protect the ends of DNA from being cut off after successive divisions since each one normally removes some which is at first the telomere.

Mitochondrial mutations—MitoSENS

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 allotopic expression—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. However, a 2003 study showed that some mitochondrial proteins are too hydrophobic to survive the transport from the cytoplasm to the mitochondria, and this is perhaps one of the reasons that not all of the mitochondrial genes have migrated to the nucleus during the course of evolution.

Intracellular junk—LysoSENS

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, which is readily detected in the form of lipofuscin granules. Atherosclerosis, macular degeneration, liver spots on the skin 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.

Extracellular junk—AmyloSENS

Harmful junk protein can also accumulate outside of our cells. 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 and other amyloidoses. The oft-mentioned "toxins" that are identified as causes of many diseases most likely fit under this class.

Cell loss and atrophy—RepleniSENS

Some of the cells in our bodies cannot be replaced, or can be only replaced very slowly—more slowly than they die. This decrease in cell number affects 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 impairs the immune system. Cell depletion can be partly corrected by therapies involving exercise and growth factors. But stem cell therapy, regenerative medicine and tissue engineering are almost certainly required for any more than just partial replacement of lost cells. De Grey points out that this research of stem cell treatments is playing an increasingly important role in the international scientific community and progress is already occurring on many fronts. However, a large number of details are involved, and most such treatments are still experimental.

Cell senescence—ApoptoSENS

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. 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, as part of a process called apoptosis, to instruct cells to destroy themselves. An example is the state known as cellular senescence. Cells in this state could be eliminated by forcing them to apoptose, and healthy cells would multiply to replace them. Cell killing with suicide genes or vaccines is suggested for making the cells undertake apoptosis.

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. De Grey proposes 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 mentioned as branches of SENS are broadly supported by the medical research community, i.e. stem cell research (RepleniSENS), anti-Alzheimers research (AmyloSENS) and oncogenomics (OncoSENS), the SENS programme as a whole 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 fully implementable in the foreseeable future. Cancer may well deserve special attention as an aging-associated disease (OncoSENS), but the SENS claim that nuclear DNA damage only matters for aging because of cancer has been challenged.

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.

De Grey Technology Review controversy

Main article: De Grey Technology Review controversy

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 SENS, at the time de Grey 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 contained a reply by Aubrey de Grey and numerous comments from readers.

During June 2005 David Gobel, CEO and Co-founder of Methuselah Foundation offered Technology Review $20,000 to fund a prize competition to publicly clarify 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, 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." 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 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." Summarizing the judges' deliberations, Pontin wrote that SENS is "highly speculative" and that many of its proposals could be reproduced with the scientific technology of that period. Myhrvold described SENS as belonging to a kind of "antechamber of science" where they wait for independent vindication. 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

According to de Grey, of the roughly 150,000 people who die each day across the globe, about two thirds — 100,000 per day — die of age-related causes. In industrialized nations, the proportion is much higher, reaching 90%.

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."

SENS meetings

There have been four SENS roundtables and five 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.

On March 30–31, 2007 a North American SENS symposium was held in Edmonton, Alberta, Canada as the Edmonton Aging Symposium. Another SENS-related conference ("Understanding Aging") was held at UCLA in Los Angeles, California on June 27-29, 2008

Five SENS conferences have been held at Queens' College, 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. The third SENS conference was held in September, 2007. The fourth SENS conference was held September 3–7, 2009 and, like the first three, it was at Queens' College, Cambridge in England, organized by de Grey. Videos of the presentations are available.

SENS Foundation

Main article: SENS Foundation

The SENS 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 scientific anti-aging research.

Before March 2009, the SENS research programme was mainly pursued by the Methuselah Foundation, co-founded by Aubrey de Grey and David Gobel. The Methuselah Foundation is most notable for establishing the Methuselah Mouse Prize, a monetary prize awarded to researchers who extend the lifespan of mice to unprecedented lengths.

See also

• Aging-associated diseases
• Rejuvenation Research
• Protoscience
• American Academy of Anti-Aging Medicine

References

Bibliography

• 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 0312367066.