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.
As of 2016 the annual budget of the SENS Research Foundation is about $5 million, a tenth of that of comparable research institutions in the mainstream of aging science such as the Buck Institute. The pace of progress on work that is funded only within the SENS research community is consequently slow in comparison, and one of the principle aims of the SENS Research Foundation staff is to ensure that they are not the only group coordinating and funding this research. There is far too much to accomplish for any one organization.
The SENS research portfolio incorporates some lines of work that are well funded and widely supported, however. In the stem cell research community many groups are making progress on understanding why stem cell activity declines with age and how to safely intervene in this process. Additionally, similarly broadly supported work on the replacement of stem cells and enhancement of regeneration in aged and damaged tissue is taking place. Since the majority of potential regenerative treatments emerging from stem cell research target age-related disease, scientists must solve the problems of stem cell aging in order for therapies to work effectively. The cancer research community is as well funded and energetic as the stem cell field, and here too there are lines of work that will lead to robust treatments for many different types of cancer in time. The Alzheimer's research community is also heavily funded, and in this case the most interesting work from a SENS perspective is the development of immunotherapies to clear amyloid from the brain. This has proven to be a challenging goal, with many failures and only incremental or partial successes so far at the clinical trial stage despite the time and money invested. Still, at the end of the day the outcome will be a general technology platform that can be turned to address other forms of amyloid in the body, and thus remove their contributions to degenerative aging.
Concrete progress is also occurring in some of the less well funded areas of SENS rejuvenation biotechnologies, albeit at a far slower pace. As the explosion of interest in senescent cell clearance in just the few years from 2014 to 2016 demonstrates, however, once a field reaches the tipping point of viability and support, things can then move quite fast. In 2014 and 2015 researchers produced several technology demonstrations for senescent cell clearance drugs based on triggering programmed cell death. The studies showed benefits to health in aged laboratory mice and received considerable attention as a result. In 2015 the startup company Oisin Biotechnologies was funded based on a gene therapy approach to destroying these unwanted cells. In 2016 several existing senescent cell research groups collaborated to found UNITY Biotechnology, demonstrated 25% extension of median life span in mice engineered to destroy their own senescent cells, and went on to raise more than $100 million in venture funding. Other cellular senescence companies and research groups, some of which have eked out very slow progress with low levels of funding for a decade or more, are being invigorated by the new attention and funding coming into the field. The present brace of initiatives may or may not succeed, but either way this field of medicine has made the leap to become a part of the research mainstream.
Other portions of the SENS portfolio are also moving in the right direction, but have yet to reach the same point of critical mass as has senescent cell clearance. In late 2015, researchers funded by the SENS Research Foundation took an important step in the tools needed for serious efforts to break glucosepane cross-links that stiffen old tissue, and that work was published in the prestigious journal Science. Also in 2015 another startup was founded, Human Rejuvenation Technologies, with the aim of producing a therapy for atherosclerosis based on the results of SENS Research Foundation programs for clearance of intracellular aggregates. Further, methods of repairing mitochondrial DNA damage funded in part by the SENS Research Foundation have moved beyond the laboratory and have been under commercial development since 2013 for narrow uses in the treatment of inherited mitochondrial disorders such as Leber's hereditary optic neuropathy - but the resulting technologies will be applicable to aging. 2015 was a busy year, as that was also when Pentraxin Therapeutics announced promising results from a small human trial of a therapy to clear transthyretin amyloid, a form of amyloid implicated in cardiovascular disease and a variety of other age-related conditions.
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 29th 2016