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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

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 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.

Comments

Are these some of the targets that George Church has made reference to recently?

Posted by: Robert at June 6th, 2016 4:41 PM

Thanks Reason for a cursory list of potential treatments coming on-line via tourism. Its great to see progress, and hopefully, this progress is speeding up. Would you guess that we can expect most of these treatments to be available within 5 years, or is 10 years more realistic?

Posted by: Robert Church at June 6th, 2016 7:21 PM

This seems a bit hypey. I don't believe that the problem of in vivo gene delivery by vector has been solved.

For example, all that needs to be done to solve cystic fibrosis is for a single gene to be added to the cells lining the lungs. But this has not been achieved yet.

Posted by: Jim at June 6th, 2016 7:52 PM

Insofar as timelines go, I don't think that next ten years will be taken up by much more than the first few gene therapies making it out into widespread use. The in vivo delivery thing will be solved in the next couple of years, I'd guess, to a decent enough degree to be useful in clinical practice. Then the rest of it will be research and competition that determines the standard approaches, which will proceed in the medical tourism space in parallel with the more familiar work on inherited diseases within the regulatory system.

Then after that the next cycle of development will will focus on diversification of gene therapies, given standard practices for delivery and putting a new therapy into the market.

Also, while some of these genes and mechanisms are fairly intriguing and/or interesting, I'm doubtful that the overwhelming majority of them are worth any sort of meaningful effort. That's for all the same reasons that drug development to alter metabolism to slow aging is a waste of time. SENS should be the first approach.

Posted by: Reason at June 6th, 2016 8:46 PM

Very interesting compilation, thank you.

Posted by: Claus Elser at June 7th, 2016 1:21 AM

''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. ''

This one is very hazardous terrain and we should not try to alter it (people with IGF-1/GH KO deficiencies have serious problems).
Endocrinology is such a huge field, we know hormones but it seems the relationships are very complex (puberty, sexual capability, gonad formation, brain plasticity to hormones, speed of aging in relation to hormones (see the famous example of parasited salmon who lives 13 years and is 'reproductive capable', while the reproductive-non parasited one dies of sexual progeria at 3 years old; or in smaller form in the parasited-S.ratti nematode who lives 400 days vs non-parasited one living 20 days).
Sexual senescence is bad and endocrinology is directly linked from brain to organs to hormones - to protracted or accelerated sexual development/longevity.

The message is to maintain sexual capacity but never abuse of it (for example, one study showed that some male Japanese centenarians maintained their level of sexual testosterone, LH, FSH and DHEA which are lost with aging. The centenarians said they were 'sexually active' and enjoy being so for their life health quality at a 100+ years. Same for female ones. Still, other studies showed that women centenarians made less children than other women, thus conserved their somatic resources vs reproductive resources allowing a longer life through lowered sexual IGF/GH. And yet aging, women in menopause have loss of estrogen/sexual senescene and frailty/mortality raise. So it's not the majority, you need to keep your hormones if you want to reach a 100). Accelerated production of GH is bad, it activates excessive insulin IGF-1 axis which increases T2D, reduces SIRT/DAF/FOXO genes who activate important oxidative stress genes (SOD, NRF2...) - But LOSS of GH is just as bad
Hutchison-Guilford'S progeria children who die at 11 to 15 years old have an extreme accelerated aging (they look like children with ghastly 'dying look' of very old people phenotype). Body autopsy show thymic involution (immunosenescence), gonad atrophy (sexual senescence), pituitary shrinkage (GH loss), arteriosclerosis (vascual stiffening), cataract, skin sagg (collagen destruction/hyaluronic excretion/ECM crosslinking), grey hair, total hair loss, organ fat droplets, facial deformation, frailty, DNA damage all over...
Small stature Ashkenazi Jewish Centenarians (in Israel or Ecuadorian mix-Jewish Ashkenazis and Laron Syndrome people who reach centenarian age are rarity; most people who have underactive IGF, also have low thyroid T3/T4, no sex-drive, hypometabolic disorders and can suffer many dibilitating problems. They don't necessarily reach a 100 either, frailty gets them first. IGF prevents frailty by increasing skeletal muscle mass (sarcopenia), sex drive (infertility), brain thymus (immunosenescence, centenarians maintain a strong immune system), skeletal bone mineralization and marrow stem cell formation (osteoporosis and immune system by bone marrow immune cells working in tandem with thymus and lymphs nodes),
I understand that diabetes, an accelerated aging phenotype, is insulin IGF and blood glucose driven. But you can't just discredit it out because Calorie Restriction, Methionine Restriction and Metformin create a form of calorie restriction that reduces IGF, glucose and thus stops diabetes/accelerated aging.
In 'normal' 'base' low-levels (sufficiently low, but not extinguished either) IGF is very important for brain development, sexual development, growth development, reproductive development, neuronal maturation and survival...too many things - in humans.
In Ames dwarrf, Snell Dwarf mice, Klotho mice, GHKO mice who have little IGF and GH; and live longer than wild-type; we see that indeed insulin and glucose/nutrient/energy pathways (which create oxidative stress through excessive nutrient via elevated glycation blood glucose creating high glycated albumin and hemoglobin), that aging is acted on by IGF through hormones, GFs, GHs, acting on insulin signals, which act on survival genes (DAF/SIRT/FOXO). It is an interplay that is very intricate.
Too much it's bad, too little it's just as bad. It's a double-edge damocles sword, a constant balance reproductive resources vs somatic resources in evolutiona natural selection theory to maintain specie's individual survival.

So many elements are GH-driven (GDF11, IGF, BDNF, Neuregulin,)
IGF are a survival signal that must kept in check. Skeletal muscle fiber formation, bone marrow stem cell formation, thymus T-cell formation, TNF-a/INF-gamma production by immune system's macrophages (immunosenescence by IGF loss),
neuregulin and brain-derived neutrophic factor depend on IGF-1 acting on brain IGFR receptors.

Still, an interesting list to work on, except the GH thing which should be left untinkered, being such a huge metabolism-controling thing in mammals. Better to keep people healthy/alive instead of pushing the 'frailty/mortality with GH-KO' methods.

Posted by: CANanonymity at June 7th, 2016 1:15 PM

All this information is good and all But can't you talk in humans treatments what we can do today

Posted by: Norm at June 9th, 2016 1:51 PM

Great resource as usual Reason.

Posted by: Adam Spong at June 12th, 2016 11:40 AM

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