Intrinsic mutagenesis: A genetic approach to ageing

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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. These are associated with many age-related conditions, such as Alzheimer's disease, but it is not yet fully understood how they cause harm. Laboratories around the world are filled with long-lived rats, mice, flies, and worms, and have been since the s.

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. 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.

Intrinsic mutagenesis

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. 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.

Senescenceā€associated intrinsic mechanisms of osteoblast dysfunctions

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:. This is the only area where little needs to be done other than watch the existing research community work on the problem.

Without these mechanisms cancers cannot grow or replicate. Either drugs or gene therapies might be used to block telomere elongation genes. 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. Researchers can work to design drugs to safely break down and remove glucosepane. 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.

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.

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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.

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!


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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?


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Questions of time depend on questions of money. It might cost less than that now, given the rapid advance of biotechnology, but not enormously less. 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.

Intrinsic mutagenesis - A genetic approach to ageing | Burnet MacFarlane | Springer

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 s 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.

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 s. 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. Fight Aging! FAQ Do you want to live a longer life in good health? These various fundamental forms of damage were discovered over the past century, with the most recent verified in the late s, 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.

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.

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Their funds power the early work of the foundation, and some start their own initiatives in later years. 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.

Intrinsic mutagenesis, a genetic approach to ageing (A Wiley biomedical-health publication)

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 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. 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.