What is aging?
What are the costs and consequences of aging?
What can I do to live longer in good health?
What are the causes of aging?
How can medical science slow aging?
How can medical science reverse aging?
What is SENS and why is it so important?
What is the state of progress towards SENS treatments to reverse aging?
What other initiatives aim to do something about aging?
Why is working to slow aging a bad strategy?
How long until life-extending medical therapies are developed?
What is the best way to support research into extending healthy human life?
The simplest and most widely agreed upon definition of aging is also the least helpful: aging is a rise in the risk of death due to intrinsic causes, meaning the failure of one or more organs or systems vital to life. A person is more aged if his or her risk of death has grown over time.
For a better explanation than this we have to ask why and how aging happens. Broadly speaking there are two schools of thought on this matter. The first, dominant school argues that aging is caused by damage, forms of wear and tear to cells and tissues, and that damage leads to characteristic changes and failures in our biology. The second, lesser school argues that aging is an evolved program of characteristic changes and failures in our biology that in turn cause damage and eventual death.
It is a mark of how complex aging is under the hood that the research community can accurately measure all sorts of damage, changes, and failures that accompany aging, but still have room to argue over whether damage causes change or change causes damage.
Approximately two thirds of all deaths worldwide are due to aging and its consequences, that proportion rising to nine-tenths in wealthier countries like the US: more than 100,000 lives are lost to aging each and every day. These are rarely pleasant or easy ends. Aging progressively raises the chance of suffering a range of fatal or disabling medical conditions: cardiovascular disease, amyloidosis, dementia, and many others. Hundreds of millions of people live with ever worsening chronic pain, disability, and suffering as a result of aging.
The overwhelming majority of all medical expenditure goes towards treating the consequences of aging or providing palliative care for the aged. Further, there is an enormous opportunity cost to aging: those who become frail and unable to work might have otherwise gone on to continue earning and creating value. The amounts involved are staggering: the cost of the most common chronic medical conditions in the US amounts to ~$280 billion in expenditures and ~$1 trillion in lost productivity each and every year. The overwhelming majority of that is due to aging.
Regular exercise and the practice of calorie restriction with optimal nutrition are both shown to extend life in laboratory animals, but only calorie restriction reliably extends maximum life span in addition to raising the average. Both exercise and calorie restriction are associated with a longer life expectancy in humans, and improve short-term measures of health in humans in the same way as in laboratory animals. On the other side of the scale, becoming fat and sedentary are shown to shorten life expectancy and make health worse in laboratory animals, and are associated with that same outcome in humans. The amount and quality of evidence for these points are the gold standard against which other claims about health practices should be measured.
No presently available technique or medical technology has been shown to do anywhere near as well as exercise and calorie restriction for a basically healthy individual: any responsible physician will tell you this. So don't go hunting for silver bullets that don't exist - there are always people out there willing to sell you a lie. It's the sad truth that you can't exercise your way to a 100% chance of living to 100: a majority of even the fittest people with the best diets die of old age and its complications before reaching 90 in the environment of today's medical technology.
Medical technology is key. Progress in medical technology is the greatest determinant of how long you will live and how good your health will be when you are older. Thus the more you can do to speed development towards therapies capable of human rejuvenation the longer you will likely live, and this is something that we can all help with: learn which research should be supported, make donations, and persuade your friends. All of that exercise and calorie restriction is just there to raise the odds of living to see the day on which aging can be reversed. Without future advances in medicine, you'll age and die on roughly the same schedule as your grandparents and great-grandparents regardless of how well you look after your health.
The mainstream position in the research community is that aging is caused by an accumulation of various forms of unrepaired cellular and tissue damage. This damage then spirals out to produce evolved responses that try to compensate for damage, malfunctions in biological systems that in turn cause further harm, and so on. A few initial fundamental forms of damage spread out into many varied changes and secondary types of damage. There is considerable debate over which of these forms of damage are more important than others, and how exactly they relate to specific age-related medical conditions, but the types of damage that cause aging are fairly settled. These various fundamental forms of damage were discovered over the past century, with the most recent verified in the late 1980s, and are as follows:
1) Some tissues steadily lose cells that are not replenished and thus progressively fail in their functions with advancing age, such as the heart and areas of the brain.
2) Mutations and other haphazard alterations to our nuclear DNA occur throughout life, raising the risk of suffering just the right combination of mutations somewhere in the body that creates a cancerous cell, one that replicates uncontrollably to form tumors.
3) Our mitochondrial DNA lies outside the cell nucleus and thus accumulates damage more readily than nuclear DNA. This impairs its critical functions and leads to the creation of a small but significant population of dysfunctional cells scattered throughout the body, which cause harmful disruption to tissues and processes.
4) Some of the proteins outside our cells, such as those vital to artery walls and skin elasticity, are created early in our life and never recycled or recycled very slowly. These long-lived proteins are susceptible to chemical reactions called cross-links that glue them together or otherwise degrade their effectiveness.
5) Senescent cells are those that have suffered damage or reached the evolved limits on cell division and shut down. They should be destroyed by the immune system or by their own self-destruction programs, but over the years they nonetheless accumulate where they are not wanted, such as in the joints. Senescent cells degrade the surrounding tissue integrity and also release harmful signals that raise the odds of nearby cells becoming senescent.
6) As we age, a small handful of different proteins misfold and accumulate outside cells in clumps and fibrils known as amyloid. These are associated with many age-related conditions, such as Alzheimer's disease, but it is not yet fully understood how they cause harm.
7) A few forms of hardy waste product build up within long-lived cells, such as those of the nervous system, impairing cellular housekeeping functions and ultimately preventing a cell from doing its job or causing it to malfunction.
Laboratories around the world are filled with long-lived rats, mice, flies, and worms, and have been since the 1990s. Genetic engineering and other interventions have been used in a range of species to alter metabolic processes in order to slow down the pace of aging - to slow the rate at which damage accumulates. There are many different ways to extend life in this fashion, most producing a gain of 10-30% in life span studies of rats or mice. Some boost the operation of cellular housekeeping processes, others lower the rate at which damaging reactive molecules are generated inside cells, while still more are not yet fully understood.
It is unknown as to how great an effect these types of therapy will have in humans, but the consensus is that any gain in life span will be small in comparison to what happens in shorter-lived animals. Calorie restriction, for example, extends life in mice by up to 40%, but certainly doesn't do that in humans, even though it produces very beneficial changes in short term measures of health. Similarly, the record holder for mouse longevity involves disabling the growth hormone receptor gene, resulting in dwarf mice that live 60-70% longer than their peers. A similar population exists as a result of a natural mutation in humans: Laron-type dwarfs, who are resistant to cancer and diabetes, but who do not appear to live any longer than the rest of us.
The path towards creating a therapy based on a method of slowing aging in laboratory animals involves searching for or designing drug candidates that can recreate some of the genetic changes made in laboratory animals, and which have minimal side effects. So far this process has yet to produce a result that has made it to the clinic, but that's really just a matter of time. Drug development is a highly regulated, very expensive, and very slow process.
If aging is caused by damage, then reversal of aging - rejuvenation - can be achieved by repairing that damage. This would involve creating targeted therapies and new forms of medical biotechnology that are somewhat more sophisticated than the mainstream drug-based medicine of today. Fortunately, it is the case that for every form of damage described above there is at least one known method of repair: these repair therapies can be described today in great detail, and all that stands between us and rejuvenation is the work needed to validate and develop these new medical technologies.
SENS stands for the Strategies for Engineered Negligible Senescence, a detailed research plan that outlines how to develop therapies capable of repairing all of the forms of cellular and molecular damage that cause aging. Once realized this package of therapies will be capable of reversing the degenerative effects of aging in the old, producing actual rejuvenation. Development and growth of the less well funded lines of SENS research is largely coordinated by the SENS Research Foundation, a charitable organization supported by prominent philanthropists and noted researchers. Other SENS projects have much better and broader support, and a growing number of independent research groups and companies are working on aspects of the whole. The SENS Research Foundation funds research groups in well-known laboratories in the US and Europe and its founders regularly advocate for more resources to be directed towards the goal of human rejuvenation.
Each of the fundamental forms of damage that together cause aging is addressed in the SENS plan and is the subject of ongoing scientific research and in some cases development of clinical therapies:
1) Stem cell research and regenerative medicine are providing very promising answers to degeneration caused by cell loss. This is the only area where little needs to be done other than watch the existing research community work on the problem.
2) SENS proposes the removal of all telomere-lengthening mechanisms as a way to eliminate cancer as a possibility in human biology. Without these mechanisms cancers cannot grow or replicate. Either drugs or gene therapies might be used to block telomere elongation genes.
3) The SENS approach to mitochondrial DNA damage is to use gene therapy to copy mitochondrial DNA into the cellular nucleus. A number of other potential strategies exist to replace or repair mitochondria and their DNA; there are many options for the near future treatment of this form of damage.
4) The chemical gunk that glues together and alters vital proteins in the extracellular matrix outside our cells, producing harmful effects such as stiffening of blood vessels, is overwhelmingly made up of a compound called glucosepane. Researchers can work to design drugs to safely break down and remove glucosepane.
5) A number of strategies can be used to selectively destroy senescent cells, many of which are presently under development in the cancer research community: there are many similarities between methods that might be used to identify and destroy cancer cells versus senescent cells. For example, researchers could instruct a patient's immune cells to target senescent cells for destruction based on their distinctive surface chemistry, a technique that is very much an ongoing concern in cancer research.
6) Immune therapies are also a potential way to target and destroy amyloid, and are currently under development as a treatment for Alzheimer's disease, a condition featuring prominent amyloid plaques.
7) To break down and remove resilient metabolic waste inside our cells, scientists can work to identify bacterial enzymes to efficiently perform the cleanup tasks that the body cannot handle. We know that these enzymes exist because no residues of these damaged proteins remain in graveyards and other, similar locations.
SENS is important because despite progress in science and advocacy it remains one of the very few rallying points within the scientific community for those interested in creating the means for human rejuvenation, and certainly still the most important of these groups. It is the only organization accepting charitable donations specifically to fund the research needed to realize rejuvenation therapies. Further, at this point the cost of completing all of the different SENS therapies to the point at which rejuvenation trials can run for laboratory animals is comparable with the cost of trying to develop a single drug to slow aging. In fact the estimated cost of SENS has already been spent several times over in the past decade on various lines of research into age-slowing drugs, none of which have yet produced meaningful results.
Realizing SENS is also an effective way of settling the argument over the root cause of aging: is aging caused by damage, or is aging caused by genetic programs that in turn cause damage? SENS will create rejuvenation in the first case, but only produce lesser, short-lived benefits in the second. The estimated cost of creating SENS therapies is small in comparison to the ongoing cost of research aimed at resolving this question by mapping all cellular biochemistry relevant to aging, and has a much greater potential near term benefit.
The following timeline references some of the important developments and advances in rejuvenation biotechnology from recent years, from the slow and incremental start to the present more rapid pace. It is by necessity a high-level and sparse overview, an attempt to capture the bigger picture without getting dragged down into the details. Watching early stage progress in research from year to year can be a frustrating process, but as senescent cell clearance demonstrates, once a field reaches the tipping point of viability and support, things then move very rapidly.
- The first of Aubrey de Grey's collaborative papers, describing SENS as a goal-driven approach to the treatment of aging as a medical condition, is published in the Annals of the New York Academy of Sciences.
- The Methuselah Foundation is created, and the founders launch the Mprize for longevity science, a research prize aiming to spur greater interest in extending healthy life spans.
- The first SENS-focused academic conference is held in the UK under the auspices of the International Association of Biomedical Gerontology.
- The Methuselah Foundation begins to assemble the 300, a core group of donors who go on to be influential in the course of advocacy and development of rejuvenation biotechnology. Their funds power the early work of the foundation, and some start their own initiatives in later years.
- An individual whose identity remains a mystery to this day makes a $1 million donation to the Methuselah Foundation to expand the Mprize purse.
- The Methuselah Foundation begins funding (a) LysoSENS research, searching for enzymes in soil bacteria capable of consuming age-related metabolic waste, and (b) allotopic expression of mitochondrial genes, aiming to remove the consequences of mitochondrial damage in aging.
- The Methuselah Foundation sponsors the Supercentenarian Research Foundation, supporting a program of autopsies of supercentenarians. Over the next few years this demonstrates transthyretin amyloidosis to be the majority cause of death.
- Peter Thiel publicly supports SENS research with a $3.5M grant.
- Researchers first demonstrate the creation of induced pluripotent stem cells, a foundation for much of the future of regenerative medicine to replace cells lost to aging.
- The Methuselah Foundation expands allotopic expression funding to support a French research group that will go on to establish Gensight Biologics on the strength of this work. The foundation also announces the commencement of research initiatives for most of the other SENS programs: clearing senescent cells, removing metabolic waste such as amyloid and cross-links, and investigation of alternative lengthening of telomeres (ALT) in the context of cancer.
- The first US SENS conference is held at UCLA.
- The SENS Research Foundation spins off from the Methuselah Foundation to focus entirely on SENS rejuvenation research.
- GSK and Pentraxin Therapeutics begin a collaboration to develop a therapy capable of clearing transthyretin amyloid.
- The Methuselah Foundation makes its first outside investment in the Organovo tissue printing startup.
- The SENS Research Foundation's yearly budget reaches $1 million. The foundation sets up a laboratory facility in Mountain View, California for ongoing intramural research projects.
- Jason Hope pledges $500,000 to the SENS Research Foundation to start a research program aimed at developing a viable cross-link breaker for glucosepane in humans.
- Researchers find that transplanting a young thymus into an old mouse restores immune function and extends life.
- Aubrey de Grey devotes the majority of his $16.5M net worth to funding SENS research.
- The SENS Research Foundation is funding either in-house or external research projects in all of the seven strands of SENS rejuvenation research. Some are very early stage, focused on building tools or discovery, while others are building the basis for therapies.
- The first demonstration of targeted senescent cell clearance is carried out by an independent research group, producing benefits in mice with an accelerated aging condition.
- The Methuselah Foundation launches the New Organ tissue engineering initiative.
- Gensight Biologics is founded to commercialize allotopic expression of mitochondrial gene ND4, based on the research program supported initially by the Methuselah Foundation, and later the SENS Research Foundation.
- The SENS Research Foundation demonstrates bacterial enzymes that can break down 7-ketocholesterol in cell culture.
- Methuselah Foundation supported tissue printing company Organovo becomes publicly traded on NASDAQ.
- Covalent Bioscience is founded to advance work on catalytic antibodies (or catabodies) to clear the amyloid associated with Alzheimer's disease.
- Gensight Biologics raises a $32M series A round.
- The Methuselah Foundation announces a $1 million research prize for liver tissue engineering as a part of the New Organ initiative. This year the foundation also fiscally sponsors organ banking initiatives at the Organ Preservation Alliance.
- The important Hallmarks of Aging position paper is published, the authors taking a cue from the SENS rejuvenation research proposals, but carving out their own view on damage and repair.
- Google Ventures launches Calico, adding a great deal of support to aging research with the size and publicity of the investment. Unfortunately Calico goes on to focus on areas of aging research unrelated to rejuvenation.
- Cenexys is founded to work on the creation of means to selectively destroy senescent cells in aged tissues.
- The Methuselah Foundation and SENS Research Foundation provide seed funding to launch Oisin Biotechnologies, to develop a method of targeted clearance of senescent cells.
- The SENS Research Foundation begins the Rejuvenation Biotechnology conference series, bringing together industry and academia to smooth the path for development of rejuvenation therapies.
- Following the Hallmarks of Aging, leading researchers publish their Seven Pillars of Aging position, again echoing the long-standing SENS view of aging and its treatment.
- The SENS Research Foundation funds development of catabodies to break down transthyretin amyloid, and the work shows considerable promise.
- Human Rejuvenation Technologies is founded to commercialize a treatment for atherosclerosis based on SENS Research Foundation LysoSENS program approaches to clearing metabolic waste compounds.
- The SENS Research Foundation's yearly budget reaches $5 million.
- The Spiegel Lab at Yale announces a method of creating glucosepane, a vital and to this point missing tool needed to develop glucosepane cross-link breaker drugs. This work was funded by the SENS Research Foundation.
- A research team demonstrates the first senolytic drug candidates capable of selectively destroying senescent cells. The number of candidate drugs increases quite quickly after this point.
- Pentraxin Therapeutics announces positive results in a trial of targeted clearance of transthyretin amyloid. Meanwhile, evidence continues to emerge from other groups for transthyretin amyloid to have more of an impact in age-related disease that previously thought.
- SENS Research Foundation work on sabotaging ALT to suppress cancer receives more attention. Meanwhile progress is reported on the other half of telomere extension blockade, interfering in the operation of telomerase, an area in which a number of groups are participating.
- The Methuselah Foundation makes a founding investment in Leucadia Therapeutics in order to pursue a novel approach to the effective treatment of Alzheimer's disease.
- The research program producing catabodies capable of breaking down transthyretin amyloid is transferred to Covalent Bioscience for clinical development.
- Ichor Therapeutics begins commercial development of a method of clearing metabolic waste from the retina, based on technology developed in the SENS Research Foundation LysoSENS program.
- Gensight Biologics demonstrates success in a trial of mitochondrial allotopic expression of ND4 as a way to treat inherited mutations of that gene. The underlying technology is proven. SENS Research Foundation scientists, meanwhile, successfully demonstrate allotopic expression of ATP6 and ATP8.
- After more than a decade of high profile failures, amyloid-β is finally cleared from the brain in a small human study using an immunotherapy approach.
- The SENS Research Foundation crowdfunds a drug discovery program to find candidates that can interfere in ALT, and thus suppress the telomere elongation that cancer depends upon.
- Cenexys is reformed as Unity Biotechnology with a focus on senolytic drugs. The researchers involved show that clearance of senescent cells in normal mice produces 25% extension of median life span. Later in 2016, the company raises $116M in venture funding.
- Other work on removal of senescent cells across the year shows restoration of function in aged lung tissue, and improved vascular health. New evidence reinforces the role of senescent cells in osteoarthritis, as well as in atherosclerosis, immunosenescence, and diabetic retinopathy
- The Methuselah Foundation launches a $500,000 research prize for tissue engineering in collaboration with NASA.
- Michael Greve pledges $10M to fund SENS research and startup biotechnology companies that emerge from that research.
- There are now nearing ten different senolytic drug candidates with openly published evidence, and more in the pipeline.
- Oisin Biotechnologies announces that their senescent cell clearance technology can also be applied to cancerous cells, reporting successful animal studies for tumor ablation.
- Methuselah Foundation launches the Methuselah Fund to shepherd more rejuvenation-related biotechnology startups towards success. The first funded company under this new organizational umbrella is Leucadia Therapeutics, working on a way to restore natural drainage channels for cerebrospinal fluid that fail with age. This is expected to help reduce the buildup of harmful metabolic waste in the brain.
- Betterhumans, associated with the Society for the Rescue of our Elders, begins running small human pilot trials of senolytic drug candidates.
- Noted investor Jim Mellon declares aging as his next target, offers support for SENS approaches in his book Juvenescence, and begins investing in companies working on means to treat aging.
- The Pineapple Fund and Vitalik Buterin donate $4.4 million in cryptocurrency to the SENS Research Foundation.
- The influential Y Combinator venture firm launches YC Bio, aimed squarely at funding startups working on the treatment of aging. There are now at least five venture funds dedicated to investing in startups that work on the treatment of aging as a medical condition. Laura Deming expands the size her Longevity Fund and launches the Age1 incubator for companies working on aging.
- Unity Biotechnology has by mid-2018 raised an enormous amount of money, filed for IPO, and while clarifying some of the senolytic targets they are developing, has yet to report human trial results.
- Gensight Biologics is conducting phase III trials for allotopic expression of mitochondrial genes to treat inherited blindness conditions. One of the trials fails on a technicality while producing better than anticipated gain in vision for patients. That allotopic expression can work is well demonstrated by now.
- Reason launches the Repair Biotechnologies startup to work on projects in rejuvenation research.
- Cleara Biotech is founded to develop the FOXO4-DRI approach to clearing senescent cells as a therapy, and Senolytic Therapies emerges with an nanotube-based method of selectively delivery cell-killing agents to senescent cells.
- More animal data on senolytic therapies is published, providing evidence for fisetin and piperlongumine to be effective at clearing senescent cells in mice. Further evidence is also provided on the dasatinib and quercetin combination, reinforcing the data for its utility. Factions within the traditional "anti-aging" marketplace begin to take notice, and start to advocate in earnest for the widespread use of these treatments.
- Revel Pharmaceuticals launches to undertake commercial development of the work on glucosepane cross-link breaker therapies carried out by the Spiegel Lab at Yale.
- There are now four different immunotherapies demonstrated to remove some degree of amyloid from the brains of Alzheimer's patients, though further development to clinical use remains a challenge.
A number of organizations either have or continue to materially support the SENS Research Foundation in its work, such as the Thiel Foundation, Methuselah Foundation, Longecity, and a number of other philanthropic foundations with an interest in medical research. A broader range of organizations either raise funds for mainstream work aimed at slow aging, encourage greater levels of funding for aging research, or make grants to researchers in the field without any great intent to speed progress towards longer lives. You can find links to some of these organizations in the Fight Aging! resources section.
Today we stand at least 20 years from the first comprehensive suite of effective therapies to either slow aging or reverse aging, even in the best of plausible scenarios - although some parts of that suite will likely emerge sooner, such as senescent cell clearance. Many of us will be old by that time: methods of slowing aging that work by reducing the pace at which damage accumulates will do very little for someone who is already aged and very damaged. A therapy that can even partially reverse aging by repairing the damage that causes degeneration will be far more beneficial to old people. Further, a therapy that repairs damage can be used over and again as damage reoccurs with the passage of time, and will provide a benefit each time it is used. Drugs that slow aging would have to be taken on an ongoing basis, producing only a small short-lasting benefit with each dose, and the end result is still that an individual will age to death. In comparison, a set of sufficiently effective repair therapies could be undertaken once every few years to indefinitely hold off the progression of aging.
The differences in utility are very clear. So if billions of dollars and decades of time are to be spent on developing either a way to slow aging or a way to reverse aging, why not work on the obviously better solution rather than the obviously worse solution, given that the costs are in the same ballpark? The real threat to our future that I see today is that the bulk of funding and present work on human longevity is focused on drug discovery to slow aging - research that will likely result in little to no benefit for anyone entering middle age today. If you and I want to live longer, healthier lives, then work on rejuvenation must instead become the priority.
How long is a piece of string? Questions of time depend on questions of money. Over the past decade the rough estimates for a fully funded crash research program to realize SENS in mice as rapidly as possible have floated around $1-2 billion over ten to twenty years. It might cost less than that now, given the rapid advance of biotechnology, but not enormously less. Unfortunately much of the SENS portfolio is nowhere near as well funded as this: the yearly budget for the SENS Research Foundation only reached $5 million in the past few years. So it will certainly take time to increase funding across this rejuvenation research industry as a whole to the optimal levels of $100 million per year or more; this is a major undertaking involving the creation of many new major programs of medical research throughout the world. That in and of itself might require decades, and it is hard to estimate the pace of growth in the early stages of a new industry. Any number of small, happenstance choices made by today's investors and researchers might gain or lose years of future progress. Just look at senescent cell clearance, a field of aging research that languished with minimal funding and interest despite the evidence for many years until the quite recent surge in funding and attention. From a technical perspective this form of rejuvenation therapy could have taken off in the same way at near any point from the early 1990s onward, and that it didn't is simple misfortune; a case of an absence of the right people with the right views in the right place and time.
Meanwhile on the other side of the fence drug discovery programs are undertaken in search of ways to modestly slow aging. We know that it can take a decade and $1 billion to push a good drug candidate through validation and regulatory hurdles, all the way from early tests to clinical use. There are no good candidates at this time, but every sign that some may emerge in the next few years based on analogs to rapamycin. So it's not unreasonable to think that a first generation drug that might slightly slow aging in humans could emerge in the mid to late 2020s. Even at that point the research community may not be able to say whether it in fact actually slows aging in humans, however, versus definitively knowing that it produces positive changes in short-term measures of health.
Donate to the SENS Research Foundation: no other organization is doing as much to ensure that rejuvenation therapies will be developed, and there is no other place where comparatively small donations can have such a large impact on the future of medicine. You can read the Foundation's annual reports to get a very clear idea as to where your money will go.
Last updated: october 7th 2018