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Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research – Article by Reason

Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research – Article by Reason

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The New Renaissance HatReason
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Today I’ll direct your attention to a couple of videos, thematically linked by the presence of Aubrey de Grey, cofounder of the SENS Research Foundation and tireless advocate for progress towards working rejuvenation therapies. For the first of the videos, de Grey recently took part in a panel discussion involving representatives of the biotechnology industry, the research establishment, and venture capital community, with the topic being the coming development of a new industry that will develop therapies to extend healthy life and turn back aging. That industry has barely started to form its earliest and smallest stage today, as the first lines of rejuvenation research reach the point of commercial viability. There are a few startups and a lot of deep pockets yet to be convinced that this is going somewhere – though the commentary in the panel is encouraged, considering those involved.

The recent Rejuvenation Biotechnology 2016 conference hosted by the SENS Research Foundation was more along the same lines, focused on creating a foundation for the near future industry that will build and provide rejuvenation therapies. The purpose of the conference series is to help smooth the way for these treatments to move rapidly from the laboratory to the clinic, to build the necessary relationships, manage expectations, and pull in the additional support needed to make best possible progress. The conference was livestreamed over the past couple of days, and at one point Aubrey de Grey announced the just-then-and-there acceptance of the first scientific publication for the MitoSENS team at the SENS Research Foundation. They are presently in the lead, at the cutting edge, among the few groups working on the project of copying mitochondrial genes into the cell nucleus to protect them from the damage of aging. Ultimately, copying all thirteen genes should completely remove the contribution of mitochondrial damage to degenerative aging, as mitochondria will no longer become dysfunctional as their local DNA is damaged. They will get the proteins they need from the cell nucleus instead. It is a worthy project, and it is always welcome to see progress on this front.

Launching Longevity: Funding the Fountain of Youth

 

Can technology make human longevity a reality? As the pace of discovery accelerates, scientists and entrepreneurs are closing in on the Fountain of Youth. Disrupting the aging process by hacking the code of life, promises better health and longer maximum lifespans. With many layers of complexity from science to ethics, there are still skeptics placing odds against human longevity. Venture capitalists are betting on success; putting big money on the table to fund longevity startups. Google/Alphabet and drugmaker AbbVie have invested $1.5 billion on Calico, while Human Longevity Inc. recently raised $220 million from their Series B funding round. Complementing traditional venture investment, VCs like Peter Thiel and Joon Yun have established foundations and prizes to accelerate the end of aging. Why are VCs suddenly investing heavily in longevity startups? Will extended lifespan be a privilege of the wealthy or will the benefits be accessible to all? How long before these well-funded startups bring viable products to market?

 

Aubrey de Grey Announces Progress in MitoSENS

 

Ok everybody, before I introduce the next session I just wanted to make a very small, brief, but very welcome announcement. Literally half an hour ago we received some extremely good scientific news. Those of you who have been following SENS research since before the SENS Research Foundation itself even existed will know that, about a decade ago, the very first project, the very first research program that we were able to initiate – with the help of, especially, the initial donation of Peter Thiel – was to make mitochondrial mutations harmless by essentially putting backup copies of the mitochondrial DNA into the nuclear genome, modified in such way of course that the encoded proteins would be colocated back into the mitochondria to do their job. This is an idea that was first put forward more than 30 years ago, but it is an idea that despite quite a bit of initial effort, nobody was able to make work. When I first came across this concept, in fact I’d thought of it myself, it’s a pretty obvious idea really, I came to the conclusion that a lot of the despair and despondency and pessimism about this approach was premature, and that it was worth having another go, and so that was the very first project we decided to fund.

Suffice to say that it has not been quite as easy as I was hoping to make progress in that space, but progress has now been made, step by step, over the past several years, with the help especially of the absolutely amazing team we have at the research center, who work on this, headed by Matthew O’Connor. Amutha Boominathan is the number two on the team, and is absolutely indispensable, I’ve no idea where we’d be without her. So, what’s happened half an hour ago is that for the very first time in the entire history of this project, we have got far enough to have a paper accepted in a very nice journal, Nucleic Acids Research, which reports on our progress in this area. The headline result in this paper is that we are the first team ever to get two of the proteins encoded by genes in the mitochondrial DNA simultaneously functioning in the same cell line, and of course – two is equivalent to infinity for mathematicians, you know that, right? – this is extremely heartening news, and I just wanted to let you all know, thank you.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Towards a Greater Knowledge of Mitochondrial DNA Damage in Aging – Article by Reason

Towards a Greater Knowledge of Mitochondrial DNA Damage in Aging – Article by Reason

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The New Renaissance HatReason
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Today I’ll point out a very readable scientific commentary on mutations in mitochondrial DNA (mtDNA) and the importance of understanding how these mutations spread within cells. This is a topic of some interest within the field of aging research, as mitochondrial damage and loss of function is very clearly important in the aging process. Mitochondria are, among many other things, the power plants of the cell. They are the evolved descendants of symbiotic bacteria, now fully integrated into our biology, and their primary function is to produce chemical energy store molecules, adenosine triphosphate (ATP), that are used to power cellular operations. Hundreds of mitochondria swarm in every cell, destroyed by quality control processes when damaged, and dividing to make up the numbers. They also tend to promiscuously swap component parts among one another, and sometimes fuse together.

Being the descendants of bacteria, mitochondria have their own DNA, distinct from the nuclear DNA that resides in the cell nucleus. This is a tiny remnant of the original, but a very important remnant, as it encodes a number of proteins that are necessary for the correct operation of the primary method of generating ATP. DNA in cells is constantly damaged by haphazard chemical reactions, and equally it is constantly repaired by a range of very efficient mechanisms. Unfortunately mitochondrial DNA isn’t as robustly defended as nuclear DNA. Equally unfortunately, some forms of mutation, such as deletions, seem able to rapidly spread throughout the mitochondrial population of a single cell, even as they make mitochondria malfunction. This means that over time a growing number of cells become overtaken by malfunctioning mitochondria and fall into a state of dysfunction in which they pollute surrounding tissues with reactive molecules. This can, for example, increase the level of oxidized lipids present in the bloodstream, which speeds up the development of atherosclerosis, a leading cause of death at the present time.

The question of how exactly some specific mutations overtake a mitochondrial population so rapidly is still an open one. There is no shortage of sensible theories, for example that it allows mitochondria to replicate more rapidly, or gives them some greater resistance to the processes of quality control that normally cull older, damaged mitochondria. The definitive proof for any one theory has yet to be established, however. In one sense it doesn’t actually matter all that much: there are ways to address this problem through medical technology that don’t require any understanding of how the damage spreads. The SENS Research Foundation, for example, advocates the path of copying mitochondrial genes into the cell nucleus, a gene therapy known as allotopic expression. For so long as the backup genes are generating proteins, and those proteins make it back to the mitochondria, the state of the DNA inside mitochondria doesn’t matter all that much. Everything should still work, and the present contribution of mitochondrial DNA damage to aging and age-related disease would be eliminated. At the present time there are thirteen genes to copy, a couple of which are in commercial development for therapies unrelated to aging, another couple were just this year demonstrated in the lab, and the rest are yet to be done.

Still, the commentary linked below is most interesting if you’d like to know more about the questions surrounding the issue of mitochondrial DNA damage and how it spreads. This is, as noted, a core issue in the aging process. The authors report on recent research on deletion mutations that might sway the debate on how these mutations overtake mitochondrial populations so effectively.

Expanding Our Understanding of mtDNA Deletions

A challenge of mtDNA genetics is the multi-copy nature of the mitochondrial genome in individual cells, such that both normal and mutant mtDNA molecules, including selfish genomes with no advantage for cellular fitness, coexist in a state known as “heteroplasmy.” mtDNA deletions are functionally recessive; high levels of heteroplasmy (more than 60%) are required before a biochemical phenotype appears. In human tissues, we also see a mosaic of cells with respiratory chain deficiency related to different levels of mtDNA deletion. Interestingly, cells with high levels of mtDNA deletions in muscle biopsies show evidence of mitochondrial proliferation, a compensatory mechanism likely triggered by mitochondrial dysfunction. In such circumstances, deleted mtDNA molecules in a given cell will have originated clonally from a single mutant genome. This process is therefore termed “clonal expansion.”

The accumulation of high levels of mtDNA deletions is challenging to explain, especially given that mitophagy should provide quality control to eliminate dysfunctional mitochondria. Studies in human tissues do not allow experimental manipulation, but large-scale mtDNA deletion models in C. elegans have proved to be helpful, showing some conserved characteristics that match the situation in humans, as well as some divergences. Researchers have used a C. elegans strain with a heteroplasmic mtDNA deletion to demonstrate the importance of the mitochondrial unfolded protein response (UPRmt) in allowing clonal expansion of mutant mtDNAs to high heteroplasmy levels. They demonstrate that wild-type mtDNA copy number is tightly regulated, and that the mutant mtDNA molecules hijack endogenous pathways to drive their own replication.

The data suggests that the expansion of mtDNA deletions involves nuclear signaling to upregulate the UPRmt and increase total mtDNA copy number. The nature of the mito-nuclear signal in this C. elegans model may have been the transcription factor ATFS-1 (activating transcription factor associated with stress-1), which fails to be imported by depolarized mitochondria, mediates UPRmt activation by mtDNA deletions. A long-standing hypothesis proposes that deleted mtDNA molecules clonally expand because they replicate more rapidly due to their smaller size. To address this question, researchers examined the behavior of a second, much smaller mtDNA deletion molecule. They found no evidence for a replicative advantage of the smaller genome, and clonal expansion to similar levels as the larger deletion. In human skeletal muscle, mtDNA deletions of different sizes also undergo clonal expansion to the same degree. Furthermore, point mutations that do not change the size of the total mtDNA molecule also successfully expand to deleterious levels, indicating that clonal expansion is not driven by genome size. Thus, similar mechanisms may be operating across organisms. In the worm, this involves mito-nuclear signaling and activation of the UPRmt.

There is some debate over interpretation of results. One paper indicates that UPRmt allows the mutant mtDNA molecules to accumulate by reducing mitophagy. Another demonstrates that the UPRmt induces mitochondrial biogenesis and promotes organelle dynamics (fission and fusion). Both papers show that by downregulating the UPRmt response, mtDNA deletion levels fall, which may allow a therapeutic approach in humans. Could there be a similar mechanism in humans, especially since some features detected in C. elegans are also present in human tissues, including the increase in mitochondrial biogenesis and the lack of relationship between mitochondrial genome size and expansion? It is likely that there will be a similar mechanism to preserve deletions since, as in the worm, deletions persist and accumulate in human tissues, despite an active autophagic quality-control process. Although the UPRmt has not been characterized in humans as it has in the worm, and no equivalent protein to ATFS-1 has been identified in mammals, proteins such as CHOP, HSP-60, ClpP, and mtHSP70 appear to serve similar functions in mammals as those in C. elegans and suggest that a similar mechanism may be present.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Lifespan Challenge: Support the MitoSENS Mitochondrial Repair Project Research Fundraiser – Video by G. Stolyarov II

Lifespan Challenge: Support the MitoSENS Mitochondrial Repair Project Research Fundraiser – Video by G. Stolyarov II

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The New Renaissance HatG. Stolyarov II
October 21, 2015
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Mr. Stolyarov, author of “Death is Wrong” and Chief Executive of the Nevada Transhumanist Party (NTP), challenges all members of the NTP and the general public to donate to life-extension research – particularly, the ongoing MitoSENS Mitochondrial Repair Project for which crowdfunding is currently being conducted on Lifespan.io.

LifespanChallengeSign-513x396

Life Extension Advocacy Foundation Launches Lifespan.io – Press Release by Life Extension Advocacy Foundation

Life Extension Advocacy Foundation Launches Lifespan.io – Press Release by Life Extension Advocacy Foundation

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The New Renaissance HatLife Extension Advocacy Foundation
August 28, 2015

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Editor’s Note: Visit and contribute to Lifespan.io’s first crowdfunding research project, the SENS Research Foundation’s MitoSENS Mitochondrial Repair Project, here. I have personally donated $100 and encourage all supporters of life-extension research to assist this effort in reaching its $30,000 funding goal. ~ Gennady Stolyarov II, August 27, 2015

LEAF_1NEW YORK, Aug. 26, 2015 – The Life Extension Advocacy Foundation (LEAF) officially launches Lifespan.io, an online platform designed to bridge the gap between longevity researchers and the public who support breakthroughs happening in this burgeoning field.

Lifespan.io is a website designed to house today’s most promising life extension projects. People are invited to contribute financially to the ones they wish to support. This unique approach to crowdfunding gives the public the opportunity to learn about longevity research, meet the people making it happen, and allows them to be a part of promising, historical breakthroughs in life extension technologies.

Supported by biologists George Church and David Sinclair, who are members of LEAF’s Scientific Advisory Board, Lifespan.io is a collaborative environment that invites projects from a wide variety of sources.  Research organizations, nonprofit institutions, citizen scientists, as well as forprofit entities, may submit their projects. Submissions are evaluated and approved based on the legitimacy, the extent of the focus on extending healthy human lifespan, and the viability of the venture.

Organizations submitting launch projects include Harvard Medical School and the SENS Research Foundation.

LEAF President Keith Comito says, “By inviting the public to participate, the organization is creating an environment where everyone can be involved and have a stake in the results. Equitable distribution of the benefits that life extension technologies have to offer is the key to achieving the results we all want: healthier and longer lives. LEAF welcomes everyone to join us and discover more.”

LEAF also aims to educate and inform the public about longevity research and life-expanding advancements. Lifespan.io has a YouTube Channel, Facebook, and Twitter profile where people can find the latest in lifespan, aging, and longevity news. To participate in and lend support to current projects, visit www.Lifespan.io. Join the conversation with the #CrowdFundtheCure hashtag.

Those wishing to submit a project for funding consideration, or who want additional information about the various methods of promotional and scientific counseling offered by LEAF, are also invited to learn more on the website.

LEAF_2ABOUT LIFE EXTENSION ADVOCACY FOUNDATION

The Life Extension Advocacy Foundation is a nonprofit 501(C)(3) organization dedicated to promoting life extension, longevity, and aging research through crowdfunding and advocacy initiatives. Its mission is to connect the researchers and scientists developing the latest advancements with the people who support them through the Lifespan.io platform. Endorsed by top scientific leaders and experts from multiple disciplines, LEAF’s goal is to make all human life healthier and more vital, as well as longer. For more information, please visit www.Lifespan.io.

Photo – http://photos.prnewswire.com/prnh/20150825/260842

Media Contact: Desireé Duffy, Life Extension Advocacy Foundation, 6614789165, info@lifespan.io

News distributed by PR Newswire iReach: https://ireach.prnewswire.com

SOURCE: Life Extension Advocacy Foundation

Mitochondrially Targeted Antioxidant SS-31 Reverses Some Measures of Aging in Muscle – Article by Reason

Mitochondrially Targeted Antioxidant SS-31 Reverses Some Measures of Aging in Muscle – Article by Reason

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The New Renaissance Hat
Reason
May 26, 2013
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Originally published on the Fight Aging! website.

Antioxidants of the sort you can buy at the store and consume are pretty much useless: the evidence shows us that they do nothing for health, and may even work to block some beneficial mechanisms. Targeting antioxidant compounds to the mitochondria in our cells is a whole different story, however. Mitochondria are swarming bacteria-like entities that produce the chemical energy stores used to power cellular processes. This involves chemical reactions that necessarily generate reactive oxygen species (ROS) as a byproduct, and these tend to react with and damage protein machinery in the cell. The machinery that gets damaged the most is that inside the mitochondria, of course, right at ground zero for ROS production. There are some natural antioxidants present in mitochondria, but adding more appears to make a substantial difference to the proportion of ROS that are soaked up versus let loose to cause harm.

If mitochondria were only trivially relevant to health and longevity, this wouldn’t be a terribly interesting topic, and I wouldn’t be talking about it. The evidence strongly favors mitochondrial damage as an important contribution to degenerative aging, however. Most damage in cells is repaired pretty quickly, and mitochondria are regularly destroyed and replaced by a process of division – again, like bacteria. Some rare forms of mitochondrial damage persist, however, eluding quality-control mechanisms and spreading through the mitochondrial population in a cell. This causes cells to fall into a malfunctioning state in which they export massive quantities of ROS out into surrounding tissue and the body at large. As you age, ever more of your cells suffer this fate.

In recent years a number of research groups have been working on ways to deliver antioxidants to the mitochondria, some of which are more relevant to future therapies than others. For example gene therapies to boost levels of natural mitochondrial antioxidants like catalase are unlikely to arrive in the clinic any time soon, but they serve to demonstrate significance by extending healthy life in mice. A Russian research group has been working with plastinquinone compounds that can be ingested and then localize to the mitochondria, and have shown numerous benefits to result in animal studies of the SkQ series of drug candidates.

US-based researchers have been working on a different set of mitochondrially targeted antioxidant compounds, with a focus on burn treatment. However, they recently published a paper claiming reversal of some age-related changes in muscle tissue in mice using their drug candidate SS-31. Note that this is injected, unlike SkQ compounds:

Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice

Quote:

Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here we demonstrate that a single treatment with the mitochondrial targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour.

Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg/kg of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and 31 P magnetic resonance spectroscopy. Age-related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle.

These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial [ROS] emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment and eight days of SS-31 treatment led to increased whole animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.

So what is SS-31? If look at the publication history for these authors you’ll find a burn-treatment-focused open-access paper that goes into a little more detail and a 2008 review paper that covers the pharmacology of the SS compounds:

Quote:

The SS peptides, so called because they were designed by Hazel H. Sezto and Peter W. Schiler, are small cell-permeable peptides of less than ten amino acid residues that specifically target to inner mitochondrial membrane and possess mitoprotective properties. There have been a series of SS peptides synthesized and characterized, but for our study, we decided to use SS-31 peptide (H-D-Arg-Dimethyl Tyr-Lys-Phe-NH2) for its well-documented efficacy.

Studies with isolated mitochondrial preparations and cell cultures show that these SS peptides can scavenge ROS, reduce mitochondrial ROS production, and inhibit mitochondrial permeability transition. They are very potent in preventing apoptosis and necrosis induced by oxidative stress or inhibition of the mitochondrial electron transport chain. These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis, and they are remarkably free of toxicity.

Given the existence of a range of different types of mitochondrial antioxidant and research groups working on them, it seems that we should expect to see therapies emerge into the clinic over the next decade. As ever, the regulatory regime will ensure that they are only approved for use in treatment of specific named diseases and injuries such as burns, however. It’s still impossible to obtain approval for a therapy to treat aging in otherwise healthy individuals in the US, as the FDA doesn’t recognize degenerative aging as a disease. The greatest use of these compounds will therefore occur via medical tourism and in a growing black market for easily synthesized compounds of this sort.

In fact, any dedicated and sufficiently knowledgeable individual could already set up a home chemistry lab, download the relevant papers, and synthesize SkQ or SS compounds. That we don’t see this happening is, I think, more of a measure of the present immaturity of the global medical tourism market than anything else. It lacks an ecosystem of marketplaces and review organizations that would allow chemists to safely participate in and profit from regulatory arbitrage of the sort that is ubiquitous in recreational chemistry.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.  

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.

A Speculative Order of Arrival for Important Rejuvenation Therapies – Article by Reason

A Speculative Order of Arrival for Important Rejuvenation Therapies – Article by Reason

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The New Renaissance Hat
Reason
October 6, 2012
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A toolkit for producing true rejuvenation in humans will require a range of different therapies, each of which can repair or reverse one of the varied root causes of degenerative aging. Research is underway for all of these classes of therapy, but very slowly and with very little funding in some cases. The funding situation spans the gamut from that of the stem cell research community, where researchers are afloat in money and interest, to the search for ways to break down advanced glycation endproducts (AGEs), which is a funding desert by comparison, little known or appreciated outside the small scientific community that works in that field.

While bearing in mind that progress in projects with little funding is unpredictable in comparison to that of well-funded projects, I think that we can still take a stab at a likely order of arrival for various important therapies needed to reverse aging. Thus an incomplete list follows, running from the earliest to the latest arrival, with the caveat that it is based on the present funding and publicity situation. If any one of the weakly funded and unappreciated lines of research suddenly became popular and awash with resources, it would probably move up in the ordering:

1) Destruction of Senescent Cells

Destroying specific cells without harming surrounding cells is a well-funded line of research thanks to the cancer community, and the technology platforms under development can be adapted to target any type of cell once it is understood how to target its distinctive features.

The research community has already demonstrated benefits from senescent cell destruction, and there are research groups working on this problem from a number of angles. A method of targeting senescent cells for destruction was recently published, and we can expect to see more diverse attempts at this in the next few years. As soon as one of these can be shown to produce benefits in mice that are similar to the early demonstrations, then senescent cell clearance becomes a going concern: something to be lifted from the deadlocked US regulatory process and hopefully developed quickly into a therapy in Asia, accessed via medical tourism.

2) Selective Pruning and Support of the Immune System

One of the reasons for immune system decline is crowding out of useful immune cells by memory immune cells that serve little useful purpose. Here, targeted cell destruction can also produce benefits, and early technology demonstrations support this view. Again, the vital component is the array of mechanisms needed to target the various forms of immune cell that must be pruned. I expect the same rising tide of technology and knowledge that enables senescent cell targeting will lead to the arrival of immune cell targeting on much the same schedule.

Culling the immune system will likely have to be supported with some form of repopulation of cells. It is already possible to repopulate a patient’s immune system with immune cells cultivated from their own tissues, as demonstrated by the limited number of full immune system reboots carried out to cure autoimmune disorders. Alternatives to this process include some form of tissue engineering to recreate the dynamic, youthful thymus as a source of immune cells – or more adventurous processes such as cultivating thymic cells in a patient’s lymph nodes.

3) Mitochondrial Repair

Our mitochondria sabotage us. There’s a flaw in their structure and operation that causes a small but steadily increasing fraction of our cells to descend into a malfunctioning state that is destructive to bodily tissues and systems.

There are any number of proposed methods for dealing with this component of the aging process – either repairing or making it irrelevant – and a couple are in that precarious state of being just a little more solidity and work away from the point at which they could begin clinical development. The diversity of potential approaches in increasing too. Practical methods are now showing up for ways to put new mitochondria into cells, or target arbitrary therapies to the interior or mitochondria. It all looks very promising.

Further, the study of mitochondria is very broad and energetic, and has a strong presence in many areas of medicine and life science research. While few groups in the field are currently engaged in work on mitochondrial repair, there is an enormous reservoir of potential funding and workers awaiting any method of repair shown to produce solid results.

4) Reversing Stem Cell Aging

The stem cell research field is on a collision course with the issue of stem cell aging. Most of the medical conditions that are best suited to regenerative medicine, tissue engineering, and similar cell based therapies are age-related, and thus most of the patients are old. In order for therapies to work well, there must be ways to work around the issues caused by the aged biochemistry of the patient. To achieve this end, the research community will essentially have to enumerate the mechanisms by which stem cell populations decline and fail with age, and then reverse their effects.

Where stem cells themselves are damaged by age, stem cell populations will have to be replaced. This is already possible for many different types of stem cell, but there are potentially hundreds of different types of adult stem cell – and it is too much to expect for the processes and biochemistry to be very similar in all cases. A great deal of work will remain to be accomplished here even after the first triumphs involving hearts, livers, and kidneys.

Much of the problem, however, is not the stem cells but rather the environment they operate within. This is the bigger challenge: picking out all the threads of signalling, epigenetic change, and cause and effect that leads to quieted and diminished stem cell populations – and the resulting frailty as tissues are increasingly poorly supported. This is a fair sized task, and little more than inroads have been made to date – a few demonstrations in which one stem cell type has been coerced into acting with youthful vigor, and a range of research on possible processes and mechanisms to explain how an aging metabolism causes stem cells to slow down and stop their work.

The stem cell research community is, however, one of the largest in the world, and very well funded. This is a problem that they have to solve on the way to their declared goals. What I would expect to see here is for a range of intermediary stopgap solutions to emerge in the laboratory and early trials over the next decade. These will be limited ways to invigorate a few aged stem cell populations, intended to be used to boost the effectiveness of stem cell therapies for diseases of aging.

Any more complete or comprehensive solution for stem cell aging seems like a longer-term prospect, given that it involves many different stem cell populations with very different characteristics.

5) Clearing Advanced Glycation Endproducts (AGEs)

AGEs cause inflammation and other sorts of mischief through their presence, and this builds up with age. Unfortunately, research on breaking down AGEs to remove their contribution to degenerative aging has been a very thin thread indeed over the past few decades: next to no-one works on it, despite its importance, and very little funding is devoted to this research.

Now on the one hand it seems to be the case that one particular type of AGE – glucosepane – makes up 90% or more the AGEs in human tissues. On the other hand, efforts to find a safe way to break it down haven’t made any progress in the past decade, though a new initiative was launched comparatively recently. This is an excellent example of how minimally funded research can be frustrating: a field can hover just that one, single advance away from largely solving a major problem for years on end. All it takes is the one breakthrough, but the chances of that occurring depend heavily on the resources put into the problem: how many parallel lines of investigation can be followed, how many researchers are working away at it.

This is an excellent candidate for a line of research that could move upward in the order of arrival if either a large source of funding emerged or a plausible compound was demonstrated to safely and aggressively break down glucospane in cell cultures. There is far less work to be done here than to reverse stem cell aging, for example.

6) Clearing Aggregates and Lysomal Garbage

All sorts of aggregates build up within and around cells as a result of normal metabolic processes, causing harm as they grow, and the sheer variety of these waste byproducts is the real challenge. They range from the amyloid that features prominently in Alzheimer’s disease through to the many constituents of lipofuscin that clog up lysosomes and degrade cellular housekeeping processes. At this point in the advance of biotechnology it remains the case that dealing with each of the many forms of harmful aggregate must be its own project, and so there is a great deal of work involved in moving from where we stand today to a situation in which even a majority of the aggregates that build up with age can be removed.

The most promising lines of research to remove aggregates are immunotherapy, in which the immune system is trained or given the tools to to consume and destroy a particular aggregate, and medical bioremediation, which is the search for bacterial enzymes that can be repurposed as drugs to break down aggregates within cells. Immunotherapy to attack amyloid as a treatment for Alzheimer’s is a going concern, for example. Biomedical remediation is a younger and far less funded endeavor, however.

My expectation here is that some viable therapies for some forms of unwanted and harmful metabolic byproducts will emerge in the laboratory over the next decade, but that will prove to be just the start on a long road indeed. From here it’s hard for me to guess at where the 80/20 point might be in clearing aggregates: successfully clearing the five most common different compounds? Or the ten most common? Or twenty? Lipofuscin alone has dozens of different constituent chemicals and proteins, never mind the various other forms of aggregate involved in specific diseases such as Alzheimer’s.

But work is work: it can be surmounted. Pertinently, and again, the dominant issue in timing here is the lack of funding and support for biomedical remediation and similar approaches to clearing aggregates.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.  

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.