Fight Aging! Newsletter, June 13th 2016

June 13th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • A Short List of Potential Target Genes for Near-Future Gene Therapies Aimed at Slowing Aging or Compensating for Age-Related Damage and Decline
  • Multiple Independent Groups are Carrying out Trials of Allotopic Expression of Mitochondrial Genes, the Basis for a Rejuvenation Therapy
  • The Roles that Investors Play in the Development of Rejuvenation Therapies
  • Immune System Destruction and Recreation Can Cure Multiple Sclerosis
  • Proposing a Solution to the Wrong Problem in Cancer Research
  • Latest Headlines from Fight Aging!
    • Biotechnology and Longevity Science as a Development Strategy
    • A Novel Method of Mitochondrial Maintenance
    • Longer Lives Mean More Years Free from Disability
    • A Review of the Aging Epigenome
    • Enhanced Mitochondrial Transport by Gene Knockout of Syntaphilin Allows for Regrowth of Damaged Nerves
    • Neural Stem Cell Transplants in a Primate Model of Parkinson's Disease
    • A Reliable Blood Test for Early Alzheimer's Disease
    • Major Mouse Testing Program in the French Media
    • Testing the Prospects for Therapies that Target Tau Protein
    • Evidence for a Link Between Air Pollution and Stroke Risk


Based on the lengthy history of posts here at Fight Aging!, I've put together a list of potential targets for gene therapy in the near future. Here, the focus is on relevance as compensatory therapies for aging, so this list omits the wide range of inherited disorders based on single faulty genes that will account for a large proportion of the gene therapy medical industry over the next few decades. Further, Fight Aging! only samples the stream of ongoing research, and so not every line of research ends up noted here. Thus the list is far from exhaustive. If a more complete list is needed, I recommend heading over to the GenAge online database, where you will find entries for several thousand genes in various species.

Additionally, there are many classes of gene therapy that are temporary, intended to briefly improve the situation in abnormal disease states in much the same way as drugs do, and I'm skipping most of those as well. Lastly, almost all potential gene therapies at the present time aim at best to compensate for the damage of aging in one way or another, or to very modestly slow the progression of that damage by altering the operation of metabolism is ways that are still far from fully mapped. Based on the few cases where we can compare the same genetic manipulation in mice and humans, only the mice have obvious extension of life: lifespan is much more plastic in short-lived species when it comes to altering the operation of metabolism. All of that has never been as interesting to me as the SENS model of rejuvenation through repair: fixing the cell and tissue damage that causes aging rather than papering over it, an approach that can in principle produce large gains in life span in our species, but which has little to do with most of the approaches to gene therapies currently under development.

This is the Age of Gene Therapy

That said, this is an era of enthusiasm for genetics and gene therapy, in which it is becoming possible to cost-effectively edit the levels of specific proteins in specific tissues at specific times, and in response to circumstances. Given a hammer, there will be people who see every problem in terms of nails, regardless of whether or not that is the case. Proteins are coded in our genes, produced from that blueprint by the process of gene expression. Genes can be removed, altered, or duplicated, and rates of gene expression can be selectively increased or decreased. Our cells are machines and the amounts of proteins present are both machine parts and controls to the machinery: cell activity alters in response to higher or level levels of various proteins. It is an enormously complicated and interdependent set of controls, still poorly understood to be sure, but the ability to change protein levels is in principle the ability to change cell behavior. At this stage the fastest way to find out what any specific change does is to try it, first in animal studies, and then confirming in human tests. It is possible to theorize in advance, to pick plausible targets based on past evidence and experiment, but since everything in cellular biochemistry connects to everything else, no change occurs in isolation. It will have secondary and further effects, altering mechanisms and rates of gene expression for other proteins, and thus may or may not end up achieving the result that theory suggests it will.

The rapid advances in genetic editing technologies over the past few years have handed the keys to the castle to the research and development community. Where previously it was very expensive to work on gene therapies, now it is much cheaper and much easier. Only very credible paths were previously open, and merited a lot of groundwork to ensure that efforts were not wasted. Now any single gene alteration is a viable place to start experimenting. The diverse body of scientific work from the past few decades can be trawled for any of the scores of gene therapies that existing evidence suggests might be beneficial enough in humans to be worth the effort. Sadly only a few of these are associated with an sufficiently extensive set of evidence such that responsible human trials are an immediate possibility: myostatin knockout for muscle growth and telomerase gene therapies to offset some of the declines of aging. In most cases a potential target for gene therapy might have only have a couple of animal studies backing it, if that. Thus confirming research projects would be required, additional work to establish that earlier conclusions were correct, and that undesirable side-effects are not lurking in the background.

Consider, however, that a few years from now multiple companies will likely be providing a small range of gene therapies to customers via medical tourism. That is the aim of BioViva, for example, and they are scarcely alone in the community of those interested in this field. To the extent that these companies succeed, they and those who follow in their footsteps will be mining the literature for additional genes to target. There will be a rush of new research and development to pull in the most plausible candidate genes: competition will drive this process, because specific genetic alterations will quickly become standardized, commoditized, widely cross-licensed products. There will soon enough be little difference between, say, a myostatin gene therapy carried out by one clinic versus another, and so companies will have to compete in other ways. This is the root of progress.

Potential Targets for Future Gene Therapies, Speculative and Otherwise

Angiotensin-converting enzyme (ACE): Lowered levels of ACE have been shown to extend mean life span in nematode worms. ACE inhibitors are used in medicine to treat hypertension, but the mechanism by which they extend life in nematodes - not a species that has to worry about high blood pressure - remains to be explored.

Adenylyl Cyclase Type 5 (AC5): Knockout of AC5 extends life in mice, with the most plausible mechanism being increased resilience of the cardiovascular system to the various slings and arrows of aging. Many of the other aspects of AC5 knockout mice resemble those of calorie restricted mice.

AMPK: Targeted overexpression of AMPK in the intestines of flies leads to increased life span. This is an energy sensor protein, connected to the calorie restriction response of greater cell maintenance, improved health, and modestly slowed aging. A number of related methods of improving stem cell activity in fly intestines have also demonstrated extension of life span.

Angiopoietin-like 4 (ANGPTL4): A recent study suggests that a rare variant in this gene, present in less than 1% of the European population, reduces the risk of heart attack by half. The suggested mechanism involves alternations to cholesterol metabolism. This is a great example of a potential gene therapy target that still needs a fair amount of work to validate the thesis and the initial data, but having a large number of existing human carriers is a good sign on the safety front.

Angiotensin II receptor type 1 (Agtr1a): Lowering Agtr1a protein levels protects mitochondrial function and modestly extends life in mice, though as for many of these methods of somewhat slowing aging there are probably many other changes to the operation of metabolism that are as yet unexplored.

Apolipoprotein A-1: Increased amounts of this protein can be deployed to alter cholesterol metabolism in a beneficial way, slowing progression of atherosclerosis by transporting away some of the damaged lipids where they are build up in blood vessel walls.

APOE: APOE is one of the only human genes with variants that are robustly associated with greater longevity. That said, it doesn't take a very large effect to produce such an association. Perhaps some people have a 1.2% chance of reaching age 100 rather than a 1% chance; that would be enough if the effect is fairly similar in most human populations. That isn't a great gain, and to my eyes isn't something worth chasing as the basis for a gene therapy.

ARID1A: A recent accidental discovery is that gene knockout of ARID1A produces greater regenerative capacity in mice, particularly in the liver. So far there is little to say about how ARID1A knockout produces its effect, as increased regeneration is the opposite outcome from that theorized to result from this genetic alteration.

Activating transcription factor 4 (ATF4): Increased levels of ATF4 in the liver are found in many of the methods of slowing aging in laboratory species, though it is unclear whether or not that makes this protein a useful target in and of itself.

Atoh1: Increased amounts of atoh1 have been used to spur growth of hair cells in guinea pigs, making it one of a number of possible approaches to address the proximate cause of forms of age-related deafness that result from loss of these cells, rather than from other causes.

Azot: The azot gene in fruit flies is a part of a mechanism by which cells collaborate to identify damaged or dysfunctional neighbors, flagging them for destruction and replacement. Adding an extra copy of the azot gene to increase levels of the azot protein results in more effective destruction of less fit cells, and an increase in life span - in fruit flies at least. The gene and associated mechanism of quality control appears to be conserved in mammals, but there is as yet little further research leading towards trying a similar approach in mice and humans to see what happens.

BCAT-1: Inhibition of bcat-1 is shown to extend life in nematode worms, possibly via a form of hormesis or calorie restriction effect by blocking the processing of some dietary molecules.

β2 microglobulin (B2M): B2M levels rise with age, and in mice reducing the amount of B2M in older inviduals restores some of the loss of cognitive decline that occurs in aging. The mechanism involved is up for debate, but the known role of B2M relates to the adaptive immune system.

BubR1: Mice engineered to express higher levels of BubR1 have lower levels of cancer, greater exercise capacity, and live modestly longer. The cancer effect makes sense in the context of what is known of BubR1, that it is involved in an important checkpoint mechanism of cellular replication, but the other outcomes are less well understood.

C-Myc: It is interesting that most of the genes involved in the recipes that produce induced pluripotency show up in this list, such as c-myc. Researchers have shown that lowered levels of c-myc can modestly slow aging and extend life in mice, with some evidence that this is due to effects on insulin metabolism, though there is a still a lot of investigation needed to take that as a firm conclusion.

C1Q: The C1Q gene plays a role in the immune system. Removing it from mice spurs greater regeneration via Wnt signaling. C1Q levels rise in the brain with aging, and again, removing it improves the state of cognitive function in later life in mice.

Catalase: Gene therapy to increase levels of the antioxidant catalase in the mitochondria in mice have produced mixed results, but some studies show improved health and extended life. Other approaches to mitochondrially targeted antioxidants have produced similar benefits. The prevailing theory is that this reduces damage to mitochondria occurring as a result of the reactive oxygen species generated within these organelles, with localized antioxidants soaking up reactive molecules before they can cause harm.

CLK1: Reduced CLK1 activity can extend life in mice due to altered mitochondrial function and consequently lowered generation of reactive oxygen species. There are many potential ways to tinker with mitochondrial operation, though I suspect there are diminishing returns to trying to combine most of them.

CRTC1: A reduced amount of CRTC1 can extend life in nematode worms, and is probably involved in the calorie restriction response. This protein is closely related to AMPK, and manipulations of both CRTC1 and AMPK are likely achieving much the same alterations in the operation of metabolism.

Cyclin A2: Increased levels of cyclin A2 have been shown to increase the regenerative capacity of heart tissue, one of an array of proteins that might for the basis for regenerative gene therapies for heart disease, and thus also might be beneficial to undergo far in advance of old age so as to slow or postpone degeneration in the heart.

FGF21: Overexpression of FGF21 occurs in the calorie restriction response, and when induced artificially using gene therapy it can extend life in mice. This is one of many methods of modestly slowing aging connected to the well-studied growth hormone/insulin-like growth factor-1 signaling pathway.

FKBP1b: Gene therapy to boost levels of FKBP1b to youthful levels can reverse age-related dysfunction of calcium metabolism in the brains of rats. Cognitive function improved as a result, as assessed with tests of spatial memory.

Follistatin: Increased follistatin produces increased muscle growth, a potentially useful compensation for the loss of muscle mass and strength that occurs with aging. It is the flip-side of myostatin, as increased follistatin blocks the activity of myostatin: either increased follistatin or reduced myostatin produce similar outcomes in animal studies, with treated individuals demonstrating increased muscle mass. Follistatin interventions are not as well studied as myostatin interventions, but follistatin increase rather than myostatin decrease was the therapeutic approach chosen by BioViva for development.

FOXO3: A variant of FOXO3 is associated with a modest reduction in cardiovascular disease and mortality in human data. FOXO3 is involved in many relevant mechanisms, so there is plenty of room to debate cause and consequence here, and little in the way of settled answers.

FOXN1: Increased levels of FOXN1 act to in the aging thymus. The thymus is where immune cells mature, and thus this intervention improves immune function in later life by increasing the supply of new immune cells. Immune aging and dysfunction results in part from there being only a small supply of such new cells, so any method of increasing that supply will probably prove useful.

GDF11: Higher levels of GDF11 have been shown to improve numerous measures of aging in mice, such as heart function, exercise capacity, and sense of smell. This is most likely occurring due to increased stem cell activity, though there continues to be some debate as to what exactly the researchers are observing in these studies. The identification of GDF11 is one of the outcomes of the increased interest in parabiosis experiments in recent years.

GHK: The level of GHK in blood and tissues declines with aging, and is implicated in some of the detrimental changes in wound healing that occur in later life. Since delivering GHK on its own appears to be beneficial, using gene therapy to reset GHK levels may restore some of this loss of regenerative capacity.

Glycine N-methyltransferase (Gnmt): In flies, higher levels of Gnmt act to inhibit the use of methionine in protein synthesis, which mimics some of the efforts of calorie restriction on health and longevity. Reaction to lower methionine levels - or the appearance of lower methionine levels - is a key trigger for the calorie restriction response.

Growth hormone / growth hormone receptor / insulin-like growth factor / insulin receptor: The longest lived genetically altered mice are those without a functional growth hormone receptor gene. They are small and vulnerable to cold, but otherwise healthy. Many similar approaches to disrupting the well-studied operations of growth hormone and insulin metabolism also extend life in mice to various degrees, some of which are whole-body, while others are tissue-specific. There is a small human population of growth hormone receptor loss of function mutants, people with Laron syndrome. They do not appear to live any longer than the rest of us, which is a caution for anyone extrapolating effects from mice, and have a variety of medical issues associated with their form of dwarfism, but may be resistant to some forms of age-related disease. If so it isn't large enough to immediately leap out from the data, however. That data is still being gathered, but it is interesting to consider what might result from a gene therapy to interfere with growth hormone and insulin metabolism in adulthood.

Histone deacetylase 2 (HDAC2): Mice engineered to have low levels of - or entirely absent - HDAC2 have improved memory function and neural plasticity.

Heat shock proteins: Heat shock proteins are molecular chaperones involved in cellular housekeeping processes that clear out damaged or misfolded proteins. Their activity increases in response to heat, toxins, and various other forms of cellular stress, and dialing up the activity of heat shock proteins is involved in a number of methods demonstrated to slow aging in laboratory animals. Many of these invoke altering the level of other proteins that interact with or regulate heat shock proteins.

Hepatic transcription factors: A range of transcription factors are associated with development and regeneration in the liver. Researchers have demonstrated that some of these can be upregulated to reduce liver fibrosis by steering cell lineages away from the production of scar tissue and towards the production of useful liver cells.

Hepatocyte growth factor (HGF): Currently under development as a potential compensatory therapy to spur remodeling and regrowth of blood vessels in ischemic disease.

INDY: The INDY gene, I'm Not Dead Yet, was one of the first longevity-associated genes discovered in flies. Reduced levels of the INDY protein extend life, with the evidence pointing to increased intestinal stem cell function as the cause.

Interleukin-21 (IL-21): Delivering higher levels of IL-21 has been demonstrated to improve the state of the immune system by increasing the pace at which new immune cells are generated. Loss of immune function with age is an important component of age-related frailty, and even partially compensating for this decline might be very beneficial.

KLF4: Selectively lowering levels of klf4 in smooth muscle cells in blood vessel walls causes beneficial changes in the behavior of these cells. Their overreaction to damaged lipids arriving in the bloodstream is muted, which slows the progression of damage and reaction to that damage that leads towards atherosclerosis.

Klotho: Overexpression of klotho has been shown to increase life span in mice, possibly through some of the same mechanisms as calorie restriction. As for many of the methods of genetic engineering that slow aging in laboratory species, the biochemistry is very complex, the effects are not large, and there is much left to understand with regards to how it actually works.

Lamins: There are three lamin isoforms, A, B, and C. The cause of progeria, a rare condition with the appearance of accelerated aging, is a mutation in Lamin A. Much smaller amounts of malformed lamin A are found in old tissues, though it is uncertain as to whether or not this contributes in any meaningful way to the progression of aging. Intriguingly, mice engineered to produce only lamin C live modestly longer. The mechanism for this enhancement is also uncertain.

LAMP2A: The A variant of lysosome-associated membrane protein 2 is a receptor involved in the cellular maintenance processes of autophagy, but levels decrease with age, and in at least some species this appears to be one of the factors involved in the age-related decline of autophagy. Nearly a decade ago now, researchers demonstrated restoration of more youthful levels of liver function in old mice by adding a duplicate gene to increase amounts of this protein. Increased efficiency of autophagy shows up as a feature of many of the interventions shown to slow aging in animals, but this is one of the few examples in which some rejuvenation of function in old animals was observed.

Leukemia inhibitory factor (LIF): Altered LIF levels have been used to spur neural cells into greater activity that can better restore lost myelin sheathing on nerves. Since we all lose some of this sheathing with age, this is of general interest, applicable to more than just conditions such as multiple sclerosis in which a great deal of myelin is lost.

Lin28a: Increased Lin28a expression enhances regenerative capacity in mice. This is another gene that has been used in reprogramming ordinary cells to become stem cells. As for all such potential options for enhancing human biochemistry, there is the question of cancer risk to address, which may make this sort of thing a better temporary therapy than permanent change.

LOS1: LOS1 may be involved in a variety of fundamental cellular processes, ranging from protein synthesis to DNA repair. The effects of LOS1 knockout on longevity have only been explored in yeast, however, so there is a lot more work to be done to prove relevance here.

miR-195: The microRNA miR-195 interacts with telomerase, and inhibiting it has much the same beneficial effect on stem activity as increasing levels of telomerase. More stem cell activity means more regeneration, though probably also a higher risk of cancer in later life. Since stem cell activity declines with age, there are a great many research groups working on potential ways to restore that activity to youthful levels, even if only temporarily.

Mitochondrial Complex I: Partial disruption of the function of mitochondrial complex I has been shown to modestly extend life in a number of species, with the dominant theory being that this is a hormetic effect - an increase in the creation of reactive oxygen species prompts cells to react with greater repair and maintenance efforts. The degree of disruption is important: too little or too much has either no effect or a detrimental effect. Similar effects might be achieved by altering the protein machinery of this complex or others in the electron transport chain. It is certainly the case that mitochondria are important in aging, but tinkering with operation in this way seems like a low-yield approach in comparison to the SENS vision of removing the impact of mitochondrial DNA damage through allotopic expression.

Mechanistic target of rapamycin (mTOR): Alterations to the mTOR gene and levels of protein produced have been shown to modestly extend life span in several species. There are also a few synergistic genetic alterations involving mTOR and other genes discovered in lower animals that produce much larger effects. The mTOR protein is involved in many fundamental cellular processes, like many of the longevity-associated genes in laboratory species, and produces fairly sweeping alterations in cellular metabolism. Deciphering what exactly is going on under the hood is far from complete in this as in many similar longevity genes.

Myostatin: Reduced myostatin produces increased muscle growth, which may be a useful compensation for the loss of muscle mass and strength that occurs with aging. As a result of a number of natural animal lineages with this mutation, myostatin knockout is by far the most examined and tested of all potential gene therapies. There have been human trials of myostatin blockade via antibodies, for example, and there are even a few well-muscled natural human myostatin loss of function mutants.

NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC): Higher levels of NMDMC have been shown to modestly slow aging in flies, most likely through improved mitochondrial function.

NF-κB: Inhibition of this gene extends life modestly in a number of lower species, though given its involvement in immunity, inflammation, apoptosis, and other fundamental processes, there is an embarrassment of riches when it comes to trying to explain the roots of the effect. All such globally altered states of metabolism in which aging is slowed require a great deal of time and effort to explore in detail, and that remains a work in progress.

NRF2 / SKN-1: Increased levels of NRF2 in mice or its homolog SKN-1 in nematodes results in slower aging and modestly extended life spans - normally NRF2 levels decline with age. This can be achieved by manipulation of the levels of other, interacting proteins such as glutathione transferase (gGsta4). The mechanism of action here is thought to involve resistance to oxidative damage and increased quality control of damaged proteins. Interestingly, long-lived naked mole rats exhibit high levels of NRF2.

Oct4: One of the target genes used in reprogramming cells into induced pluripotent stem cells. It was recently found that Oct4 can act to stablize plaques in atherosclerosis to make the disease less deadly. This is intervening far too late in the chain of consequences for my taste. We should be removing plaques or preventing their development, not devoting a lot of effort towards making them less likely to kill you.

P16: P16 is perhaps best known as an indicator of cellular senescence, a part of the mechanisms that cause damaged cells or those at the Hayflick limit to become senescent or self-destruct. The best approach to senescent cells is to destroy them, but there are signs that targeted reductions in p16 levels can in some cases produce a net benefit, such as when used to make stem cell populations more active in old age.

P21: Both MRL mice and P21 knockout mice can regenerate small injuries with no scarring, something that most other mammals cannot achieve, and reduced levels of the p21 protein seems to be the common factor in these engineered mouse lineages. P21 is closely related to the tumor suppressor gene P53: cancer suppression and enhanced regeneration are frequently found to be opposite sides of the same coin. That makes this a challenging option for enhancements via gene therapy, though researchers working on P53 have found ways around the cancer risk issue.

P53: The protein p53 plays the role of tumor suppressor, but creating a general increase in p53 levels will, in addition to reducing cancer incidence, also accelerate aging by reducing tissue maintenance through the creation of new cells. There are, however, a number of ways in which p53 levels can be increased only when needed. One involves reduced levels of mdm2, a p53 inhibitor. Another involves an additional copy of the p53 gene, inserted without disrupting the existing regulatory process that manages p53 levels. In the latter case, engineered mice live modestly longer thanks to a lower rate of cancer.

Parkin: An increased level of parkin is one of the ways in which greater cell maintenance via autophagy can be induced, resulting in improved health and modestly extended life spans. There is a lot of support in the literature for more autophagy as an unalloyed good when it comes to health and aging. Many methods of extending life in laboratory species are associated with increased autophagy, and in some cases - such as calorie restriction - that autophagy has been shown to be necessary for life extension.

PCSK9: Loss of function mutations in PCSK9 reduce the risk of cardiovascular disease, most likely through lowered blood cholesterol levels. Proof of principle studies have been carried out in mice.

PER2: Deletion of the PER2 gene in mice, associated with the mechanisms of circadian rhythm, appears to improve DNA repair in stem cell populations relevant to the immune system, resulting in a healhier immune cell population, better immune function in old age, and a modestly extended life span. A caution here is that PER2 mutants do exist in the human population, and this mutation is associated with sleep dysfunctions.

PGC-1: Increased levels of PGC-1 in the intestinal tissues of flies extend life, possibly due to improved mitochondrial and stem cell function. Intestinal function is especially important as a determinant of fly aging and mortality, and many exploratory interventions target this organ. In mice, introducing a variant of PGC-1 produces enhanced muscle growth, most likely via its interaction with myostatin.

PHD1: The protein PHD1 serves as an oxygen sensor. Mice lacking this protein are protected from ischemic injury in stroke, suffering less cell death and recovering to a greater degree afterwards.

PEPCK: Increased levels of PEPCK achieved through genetic engineering produces mice that are much more energetic, eat more, but are also modestly longer lived than their unmodified counterparts.

PIM1: Overexpression of PIM1 in the heart produces mice that live longer by improving the ability of heart tissue to repair and maintain itself.

plasminogen activator inhibitor-1 (PAI-1): Reducing levels of PAI-1 appears to modestly slow aging, possibly by removing one aspect of the harmful impact of senescent cells. Still, outright destroying these cells is probably a better course of action than trying to safely alter our biochemistry to make their presence less terrible.

Pregnancy-associated plasma protein-A (PAPP-A): Knockout of the PAPP-A gene interferes with insulin metabolism, and produces a similar extension of health and life in mice when compared with other methods of achieving this end.

Phosphatase and tensin homolog (PTEN): Adding an extra copy of the tumor suppressor gene PTEN to mice produces lower rates of cancer, much as expected, but also increased life span. This is unusual for a tumor suppressor: most will reduce life span by inhibiting regeneration and tissue maintenance at higher levels.

RbAp48: Levels of RbAp48 fall with age in the hippocampus. Researchers have demonstrated that targeted restoration of youthful levels of this protein in old mice reversed a large fraction of age-related decline in memory function.

Reticulon 4 receptor (RTN4R): Lowered levels of RTN4R can increase plasticity in the adult brain in mice, improving recovery from brain injury and increasing the ability to learn new tasks. This appears to be a part of the mechanism by which plasticity is dialed down after childhood.

Rpd3: A reduction in Rpd3 level produces improved cardiac function and modestly increased longevity in flies, though the mechanism of action remains to be explored in more detail.

SERCA2a / SUMO-1: Increased levels of of either of these two related proteins (SUMO-1 regulates SERCA2a activity) can produce greater beneficial remodeling of blood vessels and heart tissue than would normally take place, and is thus a potential compensatory therapy that might slow the progression of many cardiovascular and circulatory diseases.

Sirtuins: The sirtuin genes were hyped up as a target for calorie restriction mimetics, but as it turned out were not all that useful in practice. Results in mice were neither large, nor reliable, nor easily replicated. The evidence for altered levels of sirtuins to produce benefits large enough to chase is very mixed, despite the occasional study showing marginal or gender-specific outcomes.

Telomerase: Increased levels of telomerase have been shown to extend life in mice, as well as reducing cancer incidence in that species. A full accounting of what is going on under the hood still remains to be accomplished, but the most plausible mechanism appears to be increased stem cell activity, while effects on cancer may involve a more active immune system - though that is only speculative theory at this point. There is a goodly amount of research and evidence for this therapy to be beneficial, but telomere dynamics in mice versus people are sufficient different to argue for caution still. Tests in dogs, pigs, or another mammal with more human-like telomere dynamic would be wise. Still, BioViva has pressed ahead with telomerase gene therapy, and factions within the research community are also aiming for the same outcome of human tests, though through more conventional channels.

TGF-β1: TGF-β1 expression rises with age, and is implicated in loss of stem cell function. Interfering in this pathway via any of the related proteins so as to reduce TGF-β1 levels may be a viable way to increase stem cell activity in later life.

Transcription factor EB (TFEB): Increased activation of TFEB spurs greater autophagy and so helps to ensure better maintenance of cells. Higher levels of autophagy seem to be an unalloyed good in near all situations, and appear as a feature of many of the ways of modestly slowing aging in laboratory species.

Troponin C: Researchers have shown that delivering a modified version of the calcium receptor troponin C into the mammalian heart can improve heart function and the performance of the cardiovascular system.

TRPV1: Gene knockout of the pain receptor TRPV1 is one of a number of methods of slowing aging and extending life in mice that appears to work through altered insulin signaling. Another potential mechanism is that this gene knockout blocks the interaction between pain receptors and chronic inflammation, a process that is thought to cause harm in old tissues and organs. Like many of the interventions that slow aging in mice, there is much left to understand about how it works. Further, it isn't clear that this is a practical intervention for people: pain is useful, and permanent suppression of pain at the receptor level is probably not the right approach.

Uncoupling proteins (UCP): Uncoupling proteins manipulate mitochondrial function in order to regulate body heat. As is the case for many proteins that interact with mitochondrial function, altered levels or genetic variants can improve health and longevity - though this is more of a balancing act for uncoupling proteins, as too much uncoupling moves quickly from being harmful to being fatal.

Urokinase (uPA): The αMUPA mouse lineage has the addition of a urokinase gene and has a longer life span as a result. The uPA gene is related to PAI-1, also in this list, and is argued to achieve life extension in mice through behavioral change - these mice eat less, and thus the calorie restriction response comes into play. It is an interesting question as to whether this sort of alteration would be beneficial in humans: would a human respond in the same way to an alteration in urges?

VEGF plus Gata4, Mef 2c, and Tbx5: A fair number of research and development efforts have focused on delivery of VEGF to spur regeneration in the cardiovascular system, and particularly in the heart, an organ with only limited regenerative capacity in mammals. One of the more effective of these attempts in rodents used a mix of VEGF, Gata4, Mef 2c, and Tbx5 to encourage scar tissue in the heart to change itself into healthy tissue.


One of the multiple classes of rejuvenation therapies that will have to be built in order to bring aging under medical control involves mitochondria. The medical community must either repair damage to mitochondrial DNA or make that damage irrelevant. Mitochondria are found in their hundreds in each of our cells, the evolved descendants of symbiotic bacteria that now perform many vital functions. They carry their own DNA, thirteen genes left over from the full genome of their ancestors. There are ways for this DNA to become damaged in the course of normal cellular operations, and some of that damage can spiral out of control to cause harm to cells and surrounding tissues. Over the years ever more cells fall victim to dysfunctional mitochondria, and the damage done mounts ever higher. This is one of the causes of aging and age-related disease.

There are, however, other types of disease that involve mitochondrial mutations, and in a world in which there is much left to be done to bring greater support to rejuvenation research, it is in the construction of therapies for inherited mitochondrial diseases where the foundational work is taking place for mitochondrial repair. Eight years ago, the Methuselah Foundation and later the SENS Research Foundation used the philanthropic donations of supporters like you and I to help fund the work of a French research group on allotopic expression of mitochondrial genes. This involves copying mitochondrial genes into the cell nucleus, edited in ways that ensure that the proteins produced find their way back to the mitochondria where they are needed. When accomplished, this can mean that damage to mitochondrial DNA no longer has any detrimental effect, as the necessary proteins are still being produced. The work of past years has since blossomed into Gensight, a venture-funded company putting considerable effort to bring this type of gene therapy to the clinic.

There is a lot of work to be done here. Each mitochondrial gene requires its own challenging recipe to make the process of allotopic expression work, but allotopic expression of even one gene of the thirteen can be used to cure inherited mitochondrial diseases involving mutations of that gene. So it is possible to build companies that work on that goal, and each mitochondrial gene successfully moved to the nucleus is one thirteenth of the way to building a rejuvenation therapy that can eliminate the contribution of mitochondrial DNA damage to aging, and rejuvenate the old who are already well down the road of suffering the consequences. At present the solidly accomplished count stands at three genes. ND4, where mutation is the one of the causes of Leber hereditary optic neuropathy (LHON) is the initial focus for Gensight, and was the first gene targeted in the research funded eight years ago. As of this year, Gensight is organizing a pair of phase III trials in LHON patients. Meanwhile, at the other end of the research and development pipeline, last month the SENS Research Foundation team announced success for ATP6 and ATP8, the end of a lengthy research initiative that has produced proof of allotopic expression for these two genes in cell cultures. Other mitochondrial genes have had allotopic expression demonstrated in yeast only, or the process of relocating proteins back to the mitochondria is only partly solved.

Gensight is not the only group working on human trials of allotopic expression of ND4 for the treatment of LHON. There are at least two other independent academic research groups with results from human trials to show that allotopic expression is a viable technology, and below you'll find links to their recent research results:

Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy

The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable.

Gene Therapy for Leber Hereditary Optic Neuropathy

In this prospective open-label trial, the study drug (self-complementary adeno-associated virus [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Visual acuity remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed.

This can all be taken as more proof to show that the SENS approach of targeted philanthropic support of critical research projects in fields that are languishing creates real results. Donating to the SENS Research Foundation and Methuselah Foundation produces meaningful results: together, we have made a difference. In this case work on allotopic expression has snowballed from a tiny, poorly supported sideline into a competitive research and development community focused on mitochondrial genes. The Gensight leadership isn't resting on its laurels and will next work on allotopic expression of ND1, one of the remaining mitochondrial genes. This is exactly what the other teams will do once they are at that stage of development. All in all this is the reassuring sight of progress, the construction of robust technology platforms that will inform the development of one very important branch of rejuvenation therapies in the years ahead, the ability to remove the harms done to us by our own mitochondria.


I notice that later this month there is a networking event for investors interested in longevity science and the opportunities to invest in the field, with Aubrey de Grey, Sonia Arrison, and some of the other folk who move in Thiel Capital circles. It is taking place in Menlo Park in the California Bay Area on the 21st:

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? Join us on June 21 to hear our panel of leading experts discuss the science and business of human longevity.

Most people have, I think, at least a sketchy idea of what it is that venture capitalists and angel investors do: they put money into young companies in exchange for an ownership stake in the hopes of making a profit. Most companies fail or settle down into a barely profitable small business, and a few succeed and grow. Investment by professionals is far from the only way that companies can be funded in their early stages, however. Founders can take loans, use debt of other sorts, their own savings, and in the rare and lucky cases nothing more than revenue from clamoring hordes of new customers in order to fund the costs of setting up and the costs of growth.

For the transition of rejuvenation research after the SENS model from laboratory to startup to clinic, the venture and angel communities are especially important, however. Much more so than for most other fields. Networking is everything, and it is no accident that the SENS Research Foundation is headquartered in the Bay Area. The community of supporters who over the past 15 years raised up the SENS initiative and other related longevity science efforts upon their collective shoulders are in large part scientists, engineers, futurists, and investors - an overlapping group in that part of the world. Scientists found companies, engineers get wealthy enough to invest, and futurists spread the word, often enough while writing code by day. All rub shoulders, and dip into one another's fields of interest. The event above is representative of many meet and greet salons held in recent years in that community, with the only difference these days being that the first startup companies implementing the first rejuvenation therapies now exist. There are now opportunities to invest for the Bay Area network, and the people who listened to the futurists and wanted this to come to pass have a chance to bend their day jobs around to help.

Investing is something that investors do moderately well - or at least those that remain investors for any length of time. There is a method and a discipline and a body of tradition and knowledge. But it arguably isn't the most important thing they can be doing at this juncture in the development of longevity science. What the investment community should do, attempts to some degree, but is very poor at accomplishing is the process of nudging along pre-commercial efforts, of funding the research that will produce a crop of companies working on the technology that they would like to see exist. This is something that will not be carried out by any of the other institutions that have traditionally funded the development of early stage companies. Yet for the most part even personally interested investors leave philanthropy in their field to other people, and thus funding for truly radical, high-risk, high-reward new research is next to non-existent. The other side of the coin, targeted funding for medical research projects with excellent prospects, or that are only a few years and a million in funding away from the leap to a candidate therapy and a startup, nudging them into the target zone, is also very thin on the ground.

This is a point that Peter Thiel has been making for a few years under the heading of "radical philanthropy." The investor community does carry out philanthropy, but in a scattershot fashion, without much organization, rigor, or discipline. There is no body of tradition and knowledge in the same way as exists for the day job of for-profit investment. So a great many philathropic ventures are ultimately largely a waste, failing to achieve practical ends because they fail to spur the practical outcome of pushing research towards the clinic. Money is poorly used. There is very little in the way of nudging promising research across the line, which is strange given that this is a very good way to be positioned as the primary investor in ventures in a field that an individual might want to see move faster.

The SENS Research Foundation and Methuselah Foundation are examples of a more ad-hoc iteration of the sort of organization that might exist were this line of thinking about research, investment, and startups taken to a more rigorous conclusion. Which is to say that launch of a company is not the start of the process, and investors should be involved well before that point if they want to better achieve their goals. Many of the donors to SENS rejuvenation research projects and Methuselah Foundation initiatives are investors themselves, and some are presently coming together as a loose community of peers to invest in the startups that are now beginning to emerge from research efforts. Yet this is still at the present time, even hard-won as it is, only one increment better than a collection of happenstance events and connections, tumbling in more or less the right direction and working out because everyone involved has much the same goal in mind - which is to say therapies to treat aging, and sooner rather than later. Building on what has been learned so far, better and more organized ways to meld philanthropy and investment might be assembled. A community with deep pockets that can build the intricate networking tools and the energetic, highly networked approach to for-profit investment that presently exists should be able to make the leap over the barrier to organize and assist the non-profit research pipeline as well.


The latest update for ongoing efforts to test destruction and recreation of the immune system in patients suffering from the autoimmune disease multiple sclerosis demonstrates that this approach is effectively a cure if the initial destruction of immune cells is comprehensive enough. Researchers have been able to suppress or kill much of the immune system and then repopulate it with new cells for about as long as the modern stem cell therapy industry has been underway, something like fifteen years or so. Methodologies have improved, but the destructive side of this process remains unpleasant and risky, something you wouldn't want to try if there was any good alternative. Yet if not for the scientific and commercial success of immunosuppressant biologics such as adalimumab, clearance and recreation of immune cell populations may well have become the major thrust of research for other prevalent autoimmune conditions such as rheumatoid arthritis. Destroying these immune cell populations requires chemotherapy, however, and with avoiding chemotherapy as an incentive for patients, and the ability to sell people drugs for life as an incentive for the medical industry, biologics won. For conditions like rheumatoid arthritis, the aim became control and minimization of symptoms rather than the search for a cure. Only in much more damaging, harmful autoimmune conditions like multiple sclerosis has this research into wiping and rebuilding the immune system continued in any significant way.

Beyond being able to pinpoint which tissues are suffering damage due to inappropriately targeted immune cells, the underlying mechanisms of most autoimmune conditions are very poorly understood. Multiple sclerosis, for example, results from immune cells attacking the myelin sheathing essential for proper nerve function. Collectively, the cells of the immune system maintain a memory of what they intend to target, that much is evident, but the structure and nature of that memory is both very complex and yet to be fully mapped to the level of detail that would allow the many types of autoimmunity to be clearly understood. That these autoimmune conditions are all very different is evidenced from the unpredictable effectiveness of today's immunosuppressant treatments - they work for some people, not so well for others. Many autoimmune diseases may well turn out to be categories of several similar conditions with different roots in different portions of the immune system.

Destruction of the immune system offers a way around present ignorance: it is an engineering approach to medicine. If immune cell populations can be removed sufficiently comprehensively, then it doesn't really matter how they are storing the bad data that produces autoimmunity. That data is gone, and won't return when immune cells are restored through cell therapies. The cost of that process today is chemotherapy, which is not to be taken lightly, as the results presented here make clear. A mortality rate of one in twenty is enough to give pause, even if you have multiple sclerosis. In the future, however, much more selective cell destruction mechanisms will be developed, such as some of those emerging from the cancer research community, approaches that will make an immune reboot something that could be undertaken in a clinic with no side-effects rather than in a hospital with all the associated damage of chemotherapy. Autoimmune diseases are far from the only reason we'd want to reboot our immune systems: as we age, the accumulated impact of infections weighs heavily upon the immune system, and its limited capacity fills with uselessly specialized cells rather than those capable of destroying new threats. Failure of the immune response is a large part of age-related frailty, leading to both chronic inflammation and vulnerability to infection, and it is something that could be addressed in large part by an evolution of this approach to autoimmune disease.

New stem cell transplantation method may halt multiple sclerosis symptoms long-term, but therapy comes with high risk

A new use of chemotherapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has fully halted clinical relapses and development of new brain lesions in 23 of 24 patients with multiple sclerosis (MS) for a prolonged period without the need for ongoing medication, according to a new phase 2 clinical trial. This is the first treatment to produce this level of disease control or neurological recovery from MS, but treatment related risks limit its widespread use. Some specialist centres offer aHSCT for MS, which involves harvesting bone marrow stem cells from the patient, using chemotherapy to suppress the patient's immune system, and reintroducing the stem cells into the blood stream to "reset" the immune system to stop it attacking the body. However, many patients relapse after these treatments, so more reliable and effective methods are needed.

Researchers tested whether complete destruction, rather than suppression, of the immune system during aHSCT would reduce the relapse rate in patients and increase long-term disease remission. They enrolled 24 patients aged 18-50 from three Canadian hospitals who had all previously undergone standard immunosuppressive therapy which did not control the MS. All patients had poor prognosis and their disability ranged from moderate to requiring a walking aid to walk 100m. The researchers used a similar method of aHSCT as is currently used, but instead of only suppressing the immune system before transplantation, they destroyed it completely using a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin. This treatment is "similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system."

The primary outcome of the study was multiple sclerosis activity-free survival at 3 years (as measured by relapses of MS symptoms, new brain lesions, and sustained progression of Expanded Disability Status Scale (EDSS) scores) which occurred in 69.6% of patients after transplantation. Out of the 24 patients, one (4%) died from hepatic necrosis and sepsis caused by the chemotherapy. Prior to the treatment, patients experienced 1.2 relapses per year on average. After treatment, no relapses occurred during the follow up period (between 4 and 13 years) in the surviving 23 patients. These clinical outcomes were mirrored by freedom from detectable new disease activity on MRI images taken after the treatment. The initial 24 MRI scans revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion. Furthermore, progressive brain deterioration typical of MS slowed to a rate associated with normal aging in 9 patients with the longest follow-up.

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial

Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT.

Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6%. With up to 13 years of follow-up after aHSCT, no relapses occurred and no lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. In summary, we describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.


Despite rapid progress in biotechnology, cancer research is an expensive and slow-moving field when it comes to results in the clinic. Many projects that absorb years in time and millions in funding produce failures or only marginal successes, little better than presently available options. Therapies developed at great cost are in any case usually only applicable to one out of the thousands of varieties and subcategories of cancer. The oppressive regulatory environment for medicine in the US serves to make these issues far worse and more costly than they might be, but the underlying nature of the field is present in all regulatory regimes. All of this makes cancer research a comparatively unattractive option to for-profit biotechnology investors, and that is a significant problem. These investors are a vital part of the machinery of the marketplace, and the funds they provide are needed to in order to start companies that work to move new medical technology from the laboratory to the clinic.

Here, some of the researchers in our longevity science community propose a financial solution to this problem, a way to better distribute risk in for-profit medical development investment so as to encourage greater participation. It is certainly true that at the present time, due to the increasingly unwise actions of those who control the monetary systems of the developed world, there is an awful lot of money sloshing around in search of returns. Even small improvements to the risk profile of biotechnology investment at the high end could pull in greater funding for the industry by ranking it more attractively in comparison to other options - and there is a growing dearth of other options for managers sitting on hundred of millions or billions or more.

Cancer megafunds with in silico and in vitro validation: Accelerating cancer drug discovery via financial engineering without financial crisis

Biomedicine faces a dilemma. Despite many recent scientific breakthroughs demonstrating a clear potential for combating cancer, there has been no significant private investment in cancer drug research and development. Both constantly rising costs and increasing rates of failures in the late stages of clinical trials have made the pharmaceutical research and development unappetizingly risky from a financial perspective.

In particular, there are two main challenges. First, on average the success rate of clinical trials is low so that the average financial yield is low. Second, the large investments required to bring a single treatment to the market lead to an all-or-nothing result: the risk is high. To increase funding for cancer research while providing adequate financial returns to investors with wide ranging risk profiles by investing in multiple clinical trials at once thereby mutualizing investments and diluting risks, the concept of a "cancer megafund" was proposed. A massive amount of investment capital would support a portfolio of many drug development projects in order to spread the risks associated with any stand-alone biomedical project. The resulting lowered default probabilities could make returns attractive to investors. By issuing Research-backed Obligations (RBOs), it could be also possible to attract both fixed-income and equity investors.

The authors go on to present options for a cancer megafund and run the mathematics to demonstrate likely outcomes. They make some suggestions as to where a few of the problems of agency and accountability lie in the matter of assembling and managing large-scale funds, and how to approve governance so as to minimize those problems. All good insofar as it goes, but I can't help but feel that this proposes a solution to entirely the wrong problem. The problem is not risk management, the problem is that most cancer research as currently conducted by the mainstream is not delivering meaningful advances at a feasible cost. If problems are to be solved, then that is the one to be solved.

I have long said that true progress in cancer research will come from greatly expanding the range of cancers that can be treated with a given technology platform. An alternative way of looking at that is to say that true progress requires crushing down the cost of delivering an advance in the capabilities of medicine for each different type of cancer. At the moment most cancer research is very specific to one subtype of cancer, and there is no reasonable expectation that the technology used can be adapted to any other cancer. This is especially true of small molecule approaches, traditional drug discovery and development, and so on. This approach to cancer isn't producing results that are sufficiently good to pull in investors like a magnet, given current costs and risks.

There is a linked set of figures to consider here: cost of development per therapy, the number of cancer types that therapy can address, the risk of failure at the end of development, and the cost to adapt the underlying technology platform to another cancer type. Right now all of those numbers are pretty terrible for most cancer research. Pulling in more funding won't change that fact, and may just serve to let the present mainstream of the research community continue along with business as usual, as carried out for cancer research over the past couple of decades. I'm personally of the opinion that a funding crunch is probably good for the community so long as it spurs a change in research strategy, given that there are a number of possible technological options to improve some of the numbers above.

The approach I favor for the mid-term future of cancer research, beyond the coming next generation of therapies largely based on immunotherapy, is some form of temporary blockade of telomere lengthening, possibly global, possibly targeted, informed by the SENS Research Foundation outline for this class of technology. Telomeres cap the ends of chromosomes, a part of the mechanism that limits the number of times a cell can divide. Telomeres lose length with each cell division, and when they become too short the cell destroys itself or becomes senescent and ceases replication. All cancers have to abuse telomere lengthening in order to grow, and there are a limited number of mechanisms responsible for that lengthening: telomerase expression and the alternative lengthening of telomeres (ALT) processes. Turn them all off, and that is that for any cancer. Not all that many research groups are working on this front at the moment, but the work that has been accomplished is promising. The prospect of deploying a truly universal cancer treatment platform for much the same cost as a single therapy for a single type of cancer, as research proceeds in the mainstream today, is very attractive. It merits a far greater level of investment than presently exists.



The adoption of high technology endeavors by less developed regions is generally considered a sensible strategy. Developing regions can in theory leapfrog over decades of incremental technological development and start in on the latest and greatest; this worked pretty well in parts of Africa for communications infrastructure, for example. It also makes a great deal of sense to attempt this for fields that are heavily regulated in the US and Europe, and thus very expensive and slow to deliver progress, as developing regions can effectively compete on cost and speed. Medicine is one of the best examples, and you can see this at work in many parts of the world, where a diverse set of efforts are underway to grow medical tourism industries or local medical research communities. It is interesting to see that some of these initiatives are leaning in the direction of targeting healthspan and life span as metrics for success, though given their very bureaucratic, top-down nature I wouldn't hold your breath waiting for useful outcomes. Innovation and technological progress, where it happens, comes from philanthropy and the marketplace, and the best thing that regulators and politicians can do is to get out of the way:

On May 25-26, 2016, there took place at the capital of the Republic of Kazakhstan a global gathering of economic and political elite - the Astana Economic Forum 2016. The speech of Kazakhstan's president made a strong point about the fact that during the 25 years of the country's existence, since its independence in 1991, the average life expectancy of the Kazakhstan people significantly increased, reaching 72 years (compared to about 64 in the early 1990s). This suggested the improving of health and longevity of the population as one of the main parameters of the country's progress.

Going from directives to practice, it transpires that some concrete state-supported steps are now being discussed in Kazakhstan that would be explicitly dedicated to improving the country's healthspan values, via strengthening national biomedical research, development and translation capabilities. A case study has been developed for a global healthspan extension program in Kazakhstan named "The Global Healthspan Extension Initiative". The focus on healthspan extension is warranted by the increasing life expectancy and the corresponding increases in the incidence of aging-related diseases, such as cancer, diabetes, heart disease and neurodegenerative diseases, despite the demonstrated improvements in healthy life expectancy. Reducing these non-communicable diseases is a key priority.

The aim of the program would be to "create a translation biotech hub (not just for basic research) in Kazakhstan with a primary focus on personalized and precision medicine. We intend to build a translation engine to drive massive biomedical innovation into the country." The underlying idea is that it may be difficult for Kazakhstan to quickly reach the advanced research and development capabilities of the current leaders in the field by following in their footsteps. But it may be easier to "leapfrog" them - to create the favorable regulatory environment and incentives to rapidly draw in and help realize the most advanced research and development ideas that are currently struggling against various "brick walls" and "glass ceilings" in theirs countries of origin. "We will perform the meta-analysis and selection of advanced and emerging technologies in the field of healthspan extension, considering their potential efficacy and safety, with the aim to solve social and economic issues." The architects of this initiative envision an end to the entrenched dichotomy between the "developing" vs. "developed" countries, but anticipated a new distinction between "innovative" and "less-innovative" countries.


Mitochondria are important in aging; some forms of damage to these organelles can produce sweeping detrimental effects when they evade quality control mechanisms. There are hundreds of mitochondria inside any given cell, and the related quality control mechanisms are thought to usually involve the destruction of an entire mitochondrion. Here researchers detail a less drastic mechanism that may act to clear damaged proteins from mitochondrial structures:

Mitochondria provide cells with energy and metabolite molecules that are essential for cell growth, and faulty mitochondria cause a number of severe genetic and age-related diseases. To maintain mitochondria in a fully working state, cells have evolved a range of quality control systems for them. For example, faulty mitochondria can be removed through a process called mitophagy. In this process, which is similar to autophagy (the process used by cells to degrade unwanted proteins and organelles), the entire mitochondrion is enclosed by a double membrane. In yeast cells this structure fuses with a compartment called the vacuole, where various enzymes degrade and destroy the mitochondrion. In animal cells an organelle called the lysosome takes the place of the vacuole. Now researchers report evidence for a new quality control mechanism that helps to protect mitochondria from age- and stress-related damage in yeast. In this mechanism, a mitochondrion can selectively remove part of its membrane to send the proteins embedded in this region to the lysosome/vacuole to be destroyed, while leaving the remainder of the mitochondrion intact.

Researchers tracked the fate of Tom70, a protein that is found in the outer membrane of mitochondria, and discovered that it accumulated in the vacuole as the yeast aged. This accumulation was not the result of mitophagy, as Tom70 was directed to the vacuole even when a gene required for mitophagy was absent. Previous reports have linked cellular aging to a decline in mitochondrial activity, which is caused by an earlier loss of pH control in the vacuole. For this reason, researchers tested whether a drug that disrupts the pH of the vacuole triggers the degradation of Tom70. This appears to be the case - the drug caused Tom70 to move from the mitochondria to the vacuole for degradation.

Before Tom70 ended up in the vacuole it accumulated in a mitochondrial-derived compartment (MDC) at the surface of the mitochondria, close to the membrane of the vacuole. The formation of this compartment depended on the machinery that drives the process by which mitochondria divide. However, the subsequent delivery of the contents of the MDC to the vacuole used factors that are required for the late stages of autophagy. The researchers found that the MDC contained Tom70 and 25 other proteins, all of which are mitochondrial membrane proteins that rely on Tom70 to import them into the mitochondrial membrane. This suggests that the MDC degradation pathway selectively removes a specific group of mitochondrial proteins. The researchers hypothesize that MDC formation is linked to metabolite imbalance, as the loss of acidity inside the vacuole prevents amino acids from being stored there. This in turn leads to a build up of amino acids in the cytoplasm that can overburden the transport proteins that import them into the mitochondria. In this scenario, the selective degradation of mitochondrial transport proteins by the MDC pathway can be seen as a response that protects the organelle against an unregulated, and potentially harmful, influx of amino acids.


A recent paper provides data to show that increases in human life expectancy, so far an incidental byproduct of improvements in medical technology and lifestyle choices rather than any deliberate attempt to tackle aging, are accompanied by an increase in years spent free from disability in later life. The current slow upward trend will soon enough become a thing of the past, as the research community is presently transitioning from ignoring aging, despite it being the cause of all age-related death and disease, to attempting to intervene in processes of aging. As this approach gains wider support, a much faster upward trend in life expectancy will take hold, characterized by leaps and bounds as new technologies are introduced, such as SENS rejuvenation therapies that repair the cell and tissue damage that lies at the root of aging.

A new study that shows that the increase in life expectancy in the past two decades has been accompanied by an even greater increase in life years free of disability, thanks in large measure to improvements in cardio-vascular health and declines in vision problems. "This suggests, for the typical person, there really is an act beyond work - that once you reach age 65, you can likely look forward to years of healthy activity. So this is good news for the vast bulk of people who can now look forward to healthier, disability free life, but it's also good news for medical care because it demonstrates the value of medical spending."

The study found that in 1992, the life expectancy of the average 65-year-old was 17.5 years, 8.9 of which were free from disability. By 2008, total life expectancy has risen to 18.8 years. In addition to the overall increase, the number of disability-free years increased, from 8.9 to 10.7, while the number of disabled years fell, from 8.6 to 8.1. Driving those changes are two major treatment areas - cardiovascular health and vision treatment. "There has been an incredibly dramatic decline in deaths and disabilities from heart disease and heart failure. "Some of it is the result of people smoking less, and better diet, but we estimate that as much as half of the improvement is because of medical care, especially statin drug treatment, which is both preventing heart attacks and improving people's recovery." Much of the improvement in vision health can be summed up in a single word - cataracts. "In the past, cataract surgery was very lengthy and technically difficult. That same surgery today can be done in an outpatient setting, so that complications and disability are significantly ameliorated. It used to be that when you turn 70, your occupation became managing your health. Now you can increasingly just live your life."


Protein levels are the controlling switches and dials of cellular behavior, and most are very dynamic in response to circumstances. One important set of circumstances is the damage that accumulates over the course of aging. Cells react to that damage with epigenetic changes, chemical decorations to DNA that alter the pace of production of various proteins. In some cases this helps to compensate for damage, in others it makes things worse. This open access paper reviews what is known of age-related epigenetic alterations:

Aging is characterized by progressive functional decline at the molecular, cellular, tissue, and organismal levels. As an organism ages, it becomes frail, its susceptibility to disease increases, and its probability of dying rises. In humans, age is the primary risk factor for a panoply of diseases including neurodegeneration, cardiovascular disease, diabetes, osteoporosis, and cancer. Over the past decades, a large body of research has shown that the molecular and cellular decline of aging can be organized into several evolutionarily conserved hallmarks or pillars of aging. For example, in yeast and animals, mitochondrial dysfunction increases with age and may contribute to the progression of aging. The hallmarks of aging are interconnected, and age-associated perturbations of one can affect others. While significant progress has been made in our understanding of aging, many outstanding questions remain: Which age-associated changes are causative? How are the hallmarks of aging related to each other, and are there "hubs" in this network? Which age-dependent changes occur first? When does aging begin? Can therapeutics slow aging or even rejuvenate some aging hallmarks in an animal at any stage during lifespan, or is there a "point of no return"?

The study of gene regulation is central to many of these questions. The regulation of gene expression is not only necessary for nearly every aspect of a cell's function, but it can be sufficient to alter cellular fate. While it is clear that many biological systems and hallmarks play a crucial role in the progression of aging, we propose that epigenomic changes are particularly important because of the following: (1) Changes in gene regulation (often through expression of a single transcription factor) have been shown to be key for cellular identity. Thus, age-associated changes in transcription regulatory networks are likely to impact the function of a cell or tissue and give rise to aging phenotypes and diseases. (2) Gene regulation is a natural "hub" in the cell. Transcription regulators and chromatin modifiers receive cytoplasmic and extracellular signals and, in turn, alter the responses of the cell in an orchestrated manner. For example, in response to proteostatic stress, protein chaperone expression increases. (3) Chromatin marks are long lasting and show a progressive change with age that persists through cellular divisions. Thus, they can act as a memory that helps to propagate age-associated cellular dysfunction. (4) Recent evidence suggests that epigenomic changes can occur extremely early in the aging process and be causative.


Scientists have explored a wide variety of avenues that might lead to greater regeneration of nerve damage in mammals. In this promising early stage research, the focus is on mitochondrial activity in nerve tissue, and the ways in which it changes after childhood development:

Researchers have discovered that boosting the transport of mitochondria along neuronal axons enhances the ability of mouse nerve cells to repair themselves after injury. Neurons need large amounts of energy to extend their axons long distances through the body. This energy - in the form of adenosine triphosphate (ATP) - is provided by mitochondria, the cell's internal power plants. During development, mitochondria are transported up and down growing axons to generate ATP wherever it is needed. In adults, however, mitochondria become less mobile as mature neurons produce a protein called syntaphilin that anchors the mitochondria in place. Researchers wondered whether this decrease in mitochondrial transport might explain why adult neurons are typically unable to regrow after injury.

The researchers initially found that when mature mouse axons are severed, nearby mitochondria are damaged and become unable to provide sufficient ATP to support injured nerve regeneration. However, when the researchers genetically removed syntaphilin from the nerve cells, mitochondrial transport was enhanced, allowing the damaged mitochondria to be replaced by healthy mitochondria capable of producing ATP. Syntaphilin-deficient mature neurons therefore regained the ability to regrow after injury, just like young neurons, and removing syntaphilin from adult mice facilitated the regeneration of their sciatic nerves after injury. "Our in vivo and in vitro studies suggest that activating an intrinsic growth program requires the coordinated modulation of mitochondrial transport and recovery of energy deficits. Such combined approaches may represent a valid therapeutic strategy to facilitate regeneration in the central and peripheral nervous systems after injury or disease."


Here is an example of ongoing work on stem cell transplants for the treatment of Parkinson's disease, in which the proximate cause of the condition is an accelerated age-related loss of a small but vital population of dopamine-generating neurons in the brain. Similar transplant therapies have been tested in a number of species, and in human patients over the past decade, but there is a great variety of possible cell sources and methodologies of treatment. Progress towards a standardized therapy emerging from all of this has been frustratingly slow.

Human parthenogenetic stem cells, derived from unfertilized oocytes, can be used to generate unlimited supply of neural stem cells for transplantation. Researchers testing the potential of cell therapy for treating Parkinson's disease (PD) has found that grafting human parthenogenetic stem cell-derived neural stem cells (hpNSCs) into non-human primates modeled with PD promoted behavioral recovery, increased dopamine concentrations in the brain, and induced the expression of beneficial genes and pathways when compared to control animals not transplanted with stem cells.

The researchers also reported that the intracerebral injection and transplantation of hpNSCs was "safe and well-tolerated" for the two transplantation test animal groups with moderate to severe PD symptoms. "Previous clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD, however the source of fetal tissue is limited and may sometimes be ethically controversial. Human parthenogenetic stem cells offer a good alternative because they can be derived without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation."

PD is characterized by a profound loss of function of the brain's basal ganglia, resulting in a loss of dopamine neurons. Experiments using stem cells have offered benefits in pre-clinical studies, but have also provided "a wide variety of patient outcomes." This study used hpNSCs because the cells demonstrate characteristics of human embryonic stem cells, but are not sourced from viable embryos, which may be destroyed in the process. Previous studies with hpNSCs had shown that the cells could also be "chemically directed" to differentiate into multipotent neural stem cells and were able to be frozen for future use. While the study was designed to determine whether the test animals showed greater improvement than the control group, researchers added that a longer outcome period than 12 months may have demonstrated continued improvement and divergence from controls.


Researchers have produced a reliable blood test for the early stages of Alzheimer's disease. Early identification of Alzheimer's disease has long been a challenge for the medical community, and only in the past few years have inroads like this been made:

Researchers have announced the development of a blood test that leverages the body's immune response system to detect an early stage of Alzheimer's disease - referred to as the mild cognitive impairment (MCI) stage - with unparalleled accuracy. In a "proof of concept" study involving 236 subjects, the test demonstrated an overall accuracy, sensitivity and specificity rate of 100 percent in identifying subjects whose MCI was actually caused by an early stage of Alzheimer's disease. "About 60 percent of all MCI patients have MCI caused by an early stage of Alzheimer's disease. The remaining 40 percent of cases are caused by other factors, including vascular issues, drug side-effects and depression. To provide proper care, physicians need to know which cases of MCI are due to early Alzheimer's and which are not."

"Our results show that it is possible to use a small number of blood-borne autoantibodies to accurately diagnose early-stage Alzheimer's. These findings could eventually lead to the development of a simple, inexpensive and relatively noninvasive way to diagnose this devastating disease in its earliest stages. It is now generally believed that Alzheimer's-related changes begin in the brain at least a decade before the emergence of telltale symptoms. To the best of our knowledge, this is the first blood test using autoantibody biomarkers that can accurately detect Alzheimer's at an early point in the course of the disease when treatments are more likely to be beneficial - that is, before too much brain devastation has occurred."

For the study, the researchers analyzed blood samples from 236 subjects, including 50 MCI subjects with low levels of amyloid-beta 42 peptide in their cerebrospinal fluid. The latter is a reliable indicator of ongoing Alzheimer's pathology in the brain and predicts a likely rapid progression to Alzheimer's. Employing human protein microarrays, each containing 9,486 unique human proteins that are used as bait to attract blood-borne autoantibodies, the researchers identified the top 50 autoantibody biomarkers capable of detecting ongoing early-stage Alzheimer's pathology in patients with MCI. In multiple tests, the 50 biomarkers were 100 percent accurate in distinguishing patients with MCI due to Alzheimer's from healthy age- and gender-matched controls. Further testing of the selected MCI biomarker panel demonstrated similar high overall accuracy rates in differentiating patients with early Alzheimer's at the MCI stage from those with more advanced, mild-moderate Alzheimer's (98.7 percent), early-stage Parkinson's disease (98.0 percent), multiple sclerosis (100 percent) and breast cancer (100 percent).


The Major Mouse Testing Program is a volunteer group focused on studying potential therapies to treat aging. They aim to carry out necessary mouse studies that the mainstream of the research community is neglecting, many of which are combinations of multiple treatments, so as to speed up the pace of progress in this field. The volunteers, researchers and advocates, are presently crowdfunding their first set of studies. With just a few weeks left in the fundraiser, I encourage you to help out and offer your support in this venture. The more of this work that is accomplished, the closer we come to clinical applications of the underlying technologies, ways to meaningfully treat aging to extend healthy life and prevent age-related disease.

People could live longer lives in health and vitality by taking new kinds of medicines that clean out their bodies of old, dysfunctional cells, says a Paris-based research group. The idea is - instead of waiting for bodily aging to make people vulnerable to diseases like Alzheimer's or cancer - to keep the body strong and healthy as long as possible. The International Longevity Alliance (ILA), a French foundation, says research increasingly points to damage and junk in the cells as crucial to the aging process whereas in the past it was thought aging was just a general 'wearing out' of the body which nothing could be done about.

The ILA's new research project - the Major Mouse Testing Program (MMTP) - will test a combination of three drugs of a new kind called senolytics, which have successfully demonstrated their ability to significantly improve the state of the cardiovascular system, lungs and skin in old mice, but have not yet been tested for the effects they are believed to have on longevity. To speed up the pace of the experiments, testing will be done in mice that have already reached middle age - 18 months old - corresponding to a person aged around 60. "Although your body ages every day, researchers are working to unlock the secrets of aging and volunteers are joining forces from all over the world to help medical research restore vitality. This could be part of a last big push against decrepitude. We want to find a way to help the body get rid of old cells that inhibit the body's natural capacity of regenerating its tissues."

The ILA is fundraising for the first batch of tests, which are being done on a voluntary basis, though costs of mice, their housing and food, and analysing the results, need to be covered. The results will be made freely available to scientists around the world. The crowdfunding model, and the fact that the project is volunteer-run, is deliberately non-traditional - no shareholders expecting a return, no grant applications which can fall foul of politics - with the hope of speeding up the rate of progress in anti-aging medicine. The current project is the MMTP's first stage, but it is planned it will lead to many more tests to develop an arsenal of proven treatments and to understand effects of combining them. The more money raised, the more substances researchers will test - some 200 promising ones have not been tested yet. Combining senolytics to clear toxic cells with stem cell therapy, to promote healing, is among the future projects planned.


This popular science article looks at efforts to build therapies that target aggregations of tau, thought to contribute to neurodegenerative conditions such as Alzheimer's disease, but also present in a range of diseases known as tauopathies. Some tauopathies may in effect come to serve as testbeds for later efforts to treat Alzheimer's by clearing tau aggregates, because the link between tau and pathology is more clear in these conditions:

About 100 times rarer than Parkinson's disease, and often mistaken for it, progressive supranuclear palsy (PSP) afflicts fewer than 20,000 people in the U.S. This little-known brain disorder is quietly becoming a gateway for research that could lead to powerful therapies for a range of intractable neurodegenerative conditions including Alzheimer's and chronic traumatic encephalopathy, a disorder linked to concussions and head trauma. All these diseases share a common feature: abnormal buildup of a protein called tau in the brains of patients. People with PSP lose the sense of balance, although unlike in Parkinson's they fall backward instead of forward. Many PSP patients also struggle with speaking and swallowing. The problems can be traced to loss of nerve cells in the brain areas responsible for those capabilities - such as the basal ganglia, brain stem and cerebral cortex. Under a microscope these are the very regions that accumulate tangled clumps of tau, a normal protein found mostly in neurons. It binds to structures called microtubules, which help move nutrients up and down the cell. But in PSP and related disorders something goes wrong: Tau proteins twist out of shape and start sticking to one another rather than stabilizing microtubules. Then, through a mysterious process, the tau clusters leave the cell, spread throughout the brain and muck up communication between neurons.

Beyond PSP, other brain diseases are also marked by abnormal tau clumps. Research on Alzheimer's has focused largely on another protein called amyloid beta, which clusters into "plaques" in the brain. But there is growing interest in tau's role. When researchers analyzed healthy young adults, healthy older adults and older adults diagnosed with "probable Alzheimer's," those with a lot of tau in the temporal lobes and neocortex - brain areas important for sensory perception and memory - were close to dementia onset whereas symptoms could still be years out for people with high amyloid. Examining the brain scans in the context of other disease markers in the same participants showed that the rise and spread of tau in the brain tracked more closely with declining mental function than did amyloid. Location seems critical, too. Whereas amyloid may show up in various brain areas, tau appears more restricted to regions associated with the cognitive deficits.

Because tau more closely aligns with the start of dementia, an effective therapeutic has "probably got to deal with the tau." In past years researchers have identified tau-binding antibodies that slow the spread of toxic tau clusters in a lab assay using cultured cells. When injected into mice engineered with a tau mutation that makes the protein clump abnormally in brain cells, triggering memory and motor problems, the antibodies reduced the clumping and improved the animals' behavior. Other approaches aim to decrease tau protein production by targeting RNA; blocking tau clustering by interfering with chemical modifications on the protein's surface; or binding microtubules in order to enhance a normal tau function that gets lost as the protein misfolds and aggregates. At present a few tau-targeting approaches are being evaluated in Alzheimer's clinical trials. But more are being tested in people with PSP. Scientists are eager to assess tau therapies in PSP for a number of reasons: First, it is a pure tauopathy. Whereas people with Alzheimer's can have tau as well as several other proteins clustering in their brains, PSP patients only have abnormal tau. Second, tau has a stronger genetic link to PSP than it does to Alzheimer's. Other reasons for testing tau drugs in PSP patients have more to do with clinical trial practicalities. If an intervention is effective, then the participants taking the study drug should deteriorate more slowly than those in the placebo group. In some diseases such as Alzheimer's, however, decline is slow and inconsistent to begin with. PSP, by comparison, runs its course more rapidly and predictably.


The challenge in linking air pollution to age-related disease and mortality risk lies in the confounding correlation with wealth. There are plausible mechanisms involving, for example, increased levels of inflammation resulting from high levels of air pollution, but regions with lower levels of air pollution tend to have much wealthier populations, and it is well known that wealth correlates with greater life expectancy, both for individuals and in societies as a whole. This study adds more statistical data to the mix:

Air pollution - including environmental and household air pollution - has emerged as a leading risk factor for stroke worldwide, associated with about a third of the global burden of stroke in 2013. The findings, from an analysis of global trends of risk factors for stroke between 1990-2013, also show that over 90% of the global burden of stroke is linked to modifiable risk factors, most of which (74%) are behavioural risk factors such as smoking, poor diet and low physical activity. The authors estimate that control of these risk factors could prevent about three-quarters of all strokes. The study is the first to analyse the global risk factors for stroke in such detail, especially in relation to stroke burden on global, regional and national levels. The researchers used data from the Global Burden of Disease Study to estimate the disease burden of stroke associated with 17 risk factors in 188 countries. They estimated the population-attributable fraction (PAF) of stroke-related disability-adjusted life years (DALYs) - ie. the estimated proportion of disease burden in a population that would be avoided if exposure to a risk factor were eliminated.

Globally, the ten leading risk factors for stroke were high blood pressure, diet low in fruit, high body mass index (BMI), diet high in sodium, smoking, diet low in vegetables, environmental air pollution, household pollution from solid fuels, diet low in whole grains, and high blood sugar. About a third (29.2%) of global disability associated with stroke is linked to air pollution (including environmental air pollution and household air pollution). This is especially high in developing countries (33.7% vs 10.2% in developed countries). In 2013, 16.9% of the global stroke burden was attributed to environmental air pollution (as measured by ambient particle matter pollution of aerodynamic diameter smaller than 2·5 μm) - almost as much as that from smoking (20.7%). From 1990 to 2013, stroke burden associated with environmental air pollution has increased by over 33%.


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