Strategies for Engineered Negligible Senescence is the term coined by British
biogerontologist Aubrey de Grey for the diverse range of regenerative medical
therapies, either planned or currently in development, for the periodical
repair of all age-related damage to human tissue with the ultimate purpose
of maintaining 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 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, and was later prefaced with the term "strategies" in
the article Time to Talk SENS: Critiquing the Immutability of Human
Aging De Grey called SENS a "goal-directed rather than
curiosity-driven" approach to the science of aging, and "an effort to
expand regenerative medicine into the territory of aging". To this end, SENS
identifies seven categories of aging "damage" and a specific regenerative
medical proposal for treating each. While many biogerontologists find it
"worthy of discussion" and SENS conferences feature important research
in the field, some contend that the ultimate goals of de Grey's programme
are too speculative given the current state of technology, referring to it as
"fantasy rather than science". Framework
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. 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." He
adds: "geriatrics is the attempt to stop damage from causing pathology;
traditional gerontology is the attempt to stop metabolism from causing damage;
and the SENS approach is to eliminate the damage periodically, so keeping its
abundance below the level that causes any 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 tissue identified
by the science of biogerontology, a 'damage' report was drawn, which in turn
formed the basis of the SENS strategy. The results fell into seven main
categories of 'damage', seven alterations whose reversal would
constitute negligible senescence: cell loss or atrophy,
oncogenic nuclear mutations and epimutations,
cell senescence, mitochondrial mutations,
Intracellular junk or junk inside cells, extracellular junk or junk outside
cells, random extracellular cross-linking.
For each of these areas SENS offers at least one strategy, 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 human trials. These strategies do not presuppose that
the underlying metabolic mechanisms of aging be fully understood, only that we
take into account the form senescence takes as directly observable to science,
and described in scientific literature.. Types of aging damage and treatment
schemes = Nuclear
mutations/epimutations—OncoSENS = These are changes to the nuclear DNA, or
to proteins which bind to the nDNA. Certain mutations can lead to cancer.
This would need to be corrected by a cure for cancer, if any is ever found.
SENS focuses on a strategy called "whole-body interdiction of lengthening
telomeres", which would be made possible by periodic regenerative medicine
treatments. = 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 cause of progressive cellular degeneration.
This would be corrected by allotopic expression—copying the DNA for
mitochondria completely within the cellular nucleus, where it is better
protected. 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. = 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
accumulate as junk inside our cells, which is detected in the form of
lipofuscin granules. Atherosclerosis, macular degeneration, liver spots on the
skin and all kinds of neurodegenerative diseases 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 accumulate outside of our cells. 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. Junk outside cells might be removed by
enhanced phagocytosis, and small drugs able 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 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.
This 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. = 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 do 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, as part of a process called apoptosis, to
instruct cells to destroy themselves. Cells in this state could be eliminated
by forcing them to apoptose, and healthy cells would 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 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, e.g., stem
cell research, anti-Alzheimers research and oncogenomics, 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, but the SENS claim that nuclear
DNA damage only matters for aging because of cancer has been challenged in
the literature as well as by material in the article DNA damage theory of aging.
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 2012, Colin Blakemore criticised Aubrey de Grey, but not SENS
specifically, in a debate hosted at the Oxford University Scientific Society.
= 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
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. Three of the five submissions 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 not be
reproduced with the scientific technology of that period. 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. 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—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. 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 six 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 was held at UCLA in Los Angeles, California on June 27-29, 2008
Six 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, 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.
The fifth was held August 31 - September 4, 2011, like the first four, it was at
Queens' College, Cambridge in England, organized by de Grey. Videos of the
presentations are available. The sixth SENS conference was held from
September 3–7, 2013. Another meeting was held in August 2014
in Santa Clara, California. 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. 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.
For 2013, The SENS Research Foundation has a research budget of approximately
$4 million annually, half of it funded by a personal contribution of $13
million of Aubrey de Grey's own wealth, and the other half coming from external
donors, with the largest external donor being Peter Thiel, and another Internet
entrepreneur Jason Hope, has recently begun to contribute comparable sums.
See also References
= Footnotes = = Bibliography =
de Grey, Aubrey; Rae, Michael. 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.