Fight Aging!

Well, here we are again, at the end of another pandemic year, a year older and - hopefully - a year wiser and more knowledgeable. I said all that really needs to be said on the topic of COVID-19 as an age-related condition at the end of last year. We might hope that, given widespread vaccination, the pandemic will become a topic of diminishing importance as the year ahead progresses, even given the present round of variants, fears, and reintroduction of restrictions.

Advocacy for Aging Research

Have we finally made significant progress in convincing the world that aging is the cause of age-related disease, that greater longevity is highly desirable, and that the treatment of aging should long have been a priority? The war on cancer is 50 years old; we can learn from it, and we must, as the war on aging had better move faster than that.

Treating aging as a medical condition is no longer the fringe idea it once was, yet the anti-aging marketplace remains a pit of snake oil and a ball and chain holding back progress, too many people are talking about only modest gains rather than the goal of radical life extension, and the majority of medicine for late life conditions still attempts the impossible of extending life without extending health. Further, all too many people think of late life disability as unavoidable, and this causes them to doubt approaches to extend life span. Still, treating aging is now explicitly the goal of research into aging. While the popular media continues to do a terrible job in explaining in the field, and governments, despite lobbying efforts, are still stuck in yesteryear, this may well be a whole new era. People are asking: should we work to end aging?

There are more patient advocates and more scientists talking about this concept, and soon there will be many physicians focused on longevity. Perhaps at some point soon the first rejuvenation technologies, such as senolytics, become so obviously beneficial that people will stop talking about ethics and just get on with preventing the suffering caused by aging and age-related disease. Priorities in research and the world at large are still not appropriate for the harms done by aging, but at least some people think that we should be aiming high, running moonshot projects to produce new therapies that will make a real difference. There is a strong economic argument for major investment in aging research and the development of therapies. The cost of failing to aggressive pursue rejuvenation therapies, both financial and measured in suffering and death, is huge.

Longevity Industry

It is interesting to look back at a January post on what to expect in the longevity industry in 2021. Investment in the industry is certainly growing, and many funds are actively creating companies rather than waiting for companies to arise. There will likely be a range of longevity industry specific SPACs soon enough, given the popularity of that approach to taking companies public. Michael Greve launched a $300M expansion of his Kizoo fund, specifically aimed at rejuvenation biotechnology after the SENS model. Apollo Ventures launched a new $180M fund, and Korify Capital launched a $100M fund a couple of months later. Cambrian Biopharma raised another $100M for their efforts. An industry advocacy group has formed, the Longevity Biotech Association.

The number of biotech startups is growing, and in Europe as well as the US. Some are very well capitalized, such as NewLimit, launched with a sizable warchest to develop in vivo reprogramming therapies. Numerous companies are now working on approaches to treat mitochondrial aging. While more funding and more biotech startups are good things, many of these companies are working on less ambitious approaches, relating to stress response upregulation or similar alterations to metabolism, or unguided drug discovery that will most likely discover more metabolic tweaks that modestly slow aging in mice. Others intend to target only skin aging to use the less costly cosmetics regulatory pathway, or work in the supplement space for similar reasons. Examples include Gerostate Alpha, Genflow Biosciences, Yuva Biosciences, Elysium Health, and the Maximon companies. Would that more groups come to choose better projects to focus on!

Various updates were noted from other companies that have been working on their projects for the past few years: Calico, Lygenesis; Selphagy; BioViva announced results from a small gene therapy trial; IntraClear Biologics; Repair Biotechnologies (a few times); Cellvie; Elastrin Therapeutics; Oisin Biotechnologies; Insilico Medicine; Revel Pharmaceuticals; Rejuvenate Bio; Leucadia Therapeutics (a few times); UNITY Biotechnology.

The Community

I have been paying less attention to events this past year, given that so many were virtual only, and virtual events offer little in the way of networking opportunities. Still, a few notes from various sources: the Aging, Geroscience and Longevity Symposium; the 7th annual AARD and 8th annual AARD meetings, as that conference series forged ahead bravely, pandemic or no pandemic; and the 2021 Longevity Week in London.

There are plenty of interviews and profile pieces to be found out there, many in video form given the Foresight Insitute salons, Live Longer World podcasts, and OnDeck Longevity community. A few that I noted: investor Ronjon Nag; James Peyer of Cambrian Bio; Aubrey de Grey, formerly of SENS Research Foundation; George Church on his broad portfolio of ventures; some notes on Jim Mellon; a profile of Michael Greve; epigenetic clocks with Morgan Levine, Steve Horvath, and Vadim Gladyshev. Also a couple of book reviews to add to that list: Ageless and Lifespan.

The SENS Research Foundation continues to do well in year end fundraisers - don't forget to donate this year! The foundation conducts important work in the field of rejuvenation, advancing neglected but important projects needed to repair the damage of aging. Earlier this year they were the recipient of more than $20M in charitable donations in connection with a cryptocurrency launch, and are hiring more scientists. The Methuselah Foundation, meanwhile, literally finds itself with more resources than it can easily access or spend, hundreds of millions of dollars at the time of writing, a result of strange machinations in the cryptocurrency space. The foundation also announced a winner for their Vascular Challange competition. Lifespan.io has extended their crowdfunding efforts to running small human trials of simple therapies, starting with mTOR inhibitors. Hopefully more to come as this approach to moving the field forward gains support.

The Forever Healthy Foundation continues to turn out great analyses of available therapies as a resource for all interested parties. The Astera Institute's Rejuvenome project launched this year, a sizable philanthropic effort to perform useful life span studies in mice that academia and industry will not get to on their own. Another new organization offers the Impetus Grants for high risk high reward aging research. The Radical Life Extension Group are performing small human trials of simple potential therapies such as plasma dilution. The Longevity Science Foundation launched in Europe with a sizable committment to research funding. Last but not least, VitaDAO is applying a distributed organization structure to funding aging research and development, and seems off to a good start.

Senolytics and Other Senotherapeutics

Senescent cells are influential enough on aging that models of aging based solely on senescent cell accumulation produce decent predictions. Accumulation of senescent cells has a bidirectional relationship with immune aging: the immune system clears senescent cells, but is harmed by their presence and inflammatory secretions. Cellular senescence spreads through tissues once established in any one location, a phenomenon possibly mediated by neutrophils. Bcl-xL is one of many senolytic drug targets, and it is found to correlate with aspects of aging in late life, also a sign of the relative importance of cellular senescence in aging. Senescent cells may explain the inverse relationship between cancer and neurodegeneration. Researchers are beginning to put numbers to senescent cell counts by age, such as in the immune system.

The number of companies working on senolytic and other senotherapeutic therapies continues to increase, as does the variety of approaches to the selective destruction of senescent cells, or the suppression of their activities, or the prevention of senescence. Those approaches include: the use of silica nanoparticles; GLS1 inhibition; activation of invariant natural killer T cells; identifying and then targeting surface markers selective for the senescent state, with candidates such as B2M; activation of the NRF2 pathway; supplementation with procyanidin C1; fisetin, still overdue for confirmation of its senolytic capacity in humans; supplementation with dihomo-γ-linoleic acid; NANOG overexpression; acid ceramidase inhibition; inhibiting IKK/NF-κB activation; piperlongumine, which continues to be comparatively poorly researched. The research and development communities are still far too slow to start clinical trials for the many age-related conditions that might be successfully treated via elimination of senescent cells from aged tissues. Nonetheless, there are some signs of progress here, such as calls for trials in cancer patients, though not everyone in the cancer research community is wholehearted enthused. Senescent cells are both helpful and harmful in the context of shutting down cancer.

Data continues to roll in to support the use of senolytics in a very wide range of conditions, even though senescent cells are likely different by tissue, and early drugs variably effective by tissue. Just in the past year, and only those that I happened to notice and discuss, by no means a comprehensive list: vascular senescence in atherosclerosis (a number of groups are looking at this), and in general as a component of vascular dysfunction; neurodegenerative conditions, as senescent microglia are found in greater numbers in the brains of patients with neurodegenerative conditions such as Alzheimer's disease, and there is a good deal of supporting evidence for senolytics to be a useful treatment for Alzheimer's; senescent cells play an important role in chronic kidney disease and loss of kidney regeneration with age; several lines of work show that senescent cells harm the sympathetic nervous system; they contribute to fatty liver disease; COVID-19 severity in the aged is mediated in part by senescent cell burden, and a trial of fisetin is underway in this context; vulnerability to inflammatory conditions is in general increased by senescent cells, not just in the case of COVID-19; senescent cells are found in skin, and thus contribute to skin aging; cartilage damage in osteoarthritis is caused in part by senescent cells; cancer severity is mediated by the relationship between cancer cells and senescent cells, and senolytics may reduce precancerous lesions; liver aging is clearly caused in part by senescent cells, as is kidney aging; also diabetic retinopathy and pulmonary fibrosis, the subject of human trials and ongoing work by several research groups; fibrosis in general can be treated with senolytic strategies; the contribution of visceral fat to insulin resistance is mediated by senescent cells; retinal aging; senescent cells may slow bone fracture repair; age-related metabolic dysfunction; disc degeneration is slowed by senolytic treatment; cellular senescence may be the mechanism linking psychological stress with cognitive decline; temporomandibular joint degeneration is caused in large part by senescent cells; type 2 diabetes accelerates degeneration via an increased burden of cellular senescence; brain aging and neurodegeneration; osteoporosis; the higher risk of failure of transplantation of old organs; the age-related decline in neurogenesis; poor outcomes in stem cell therapies due to senescence in cultured cell populations; prevention of scarring in nerve injury; gliosis and tau aggregation in tauopathies such as Alzheimer's disease.

All this said, continual clearance of senescent cells, as opposed to intermittent clearance, is probably a bad idea, as these cells do serve useful purposes when present for the short term. Thus senolytic vaccines that encourage immune destruction of senescent cells are an interesting option, but may not the right path forward. Early life use of senolytics may also be harmful over the long term. A pleasant surprise is that senolytic therapy does in fact improve muscle regeneration following injury in old mice, indicating that the negative effects of slow clearance of senescent cells in old age outweigh the negative effects of clearing those cells during the regenerative process.

Surprisingly little progress has been made on cheap, simple ways to assess the burden of senescent cells. Many different approaches have been proposed, but none are yet easily available for clinical use. Measuring extracellular vesicles from senescent cells in urine is one such proposed assay, assessing ANGPTL2 levels in blood is another. Researchers have also suggested measuring certain fatty acids that enter the blood and urine when senescent cells die.

The NIH has launched SenNet, a major research initiative in the biochemistry of cellular senescence. There is more evidence these days for mTOR inhibitors as senotherapeutics, not killing senescent cells but preventing senescence via upregulated autophagy. Naked mole-rats apparently employ cholesterol metabolism to enable cells to resist senescence, though it remains to be seen as to what can be achieved with this knowledge. It turns out that all senescent cells have genomic damage, produced on the transition into the senescent state. A last thought for this section: is exercise a mild senotherapeutic, given the evidence for a reduced burden of cellular senescence, and how about similar data for calorie restriction? Color me dubious as to the usefulness of this designation. If we start describing exercise as a rejuvenation therapy, then our bar is set far too low.

Inflammation and Other Immune Aging

The adaptive immune system ages in its own way distinct from the aging of the innate immune system, including excessive T cell expansion, disruption of naive T cell quiescence, and detrimental interactions between T cells and fat tissue that produce inflammation. Thymic involution is a noteworthy component of adaptive immune aging, and the activities of dendritic cells in response to infection may be important in this process. Persistent infection with cytomegalovirus is also important in the decline of the adaptive immune system. Researchers see CD4+/CD8+ cell ratio as a useful biomarker of immune aging.

Every aspect of immune aging should be a high priority target for intervention. Some groups are looking at ways to suppress macrophage inflammatory signaling, such via upregulation of mitochondrial uncoupling in these cells. Age-associated B cells also contribute to chronic inflammation, and might be productively cleared from the body. Memory B cells, on the other hand, decline in number and should be restored. Researchers are investigating the cGAS-STING pathway, microRNA-92a inhibition, CD40L, TLR4, MG53, and CXCL9 as targets for the suppression of unwanted inflammation in connection with various conditions.

Regrowth of the thymus is an important goal, and a step towards a small molecule approach has been made with the identification of Rac1 inhibition as a possible target. Naked mole rats undergo little thymic involution with age, and actually have three thymi rather than just one; as with many aspects of this long-lived, slowly aging species, it is a question mark as to whether there is anything useful that can be accomplished in the near term with this information. The aging of lymph nodes, coordination sites for the immune response, may turn out to be similarly important in later stages of life, limiting the degree to which a restored supply of immune cells could increase immune function.

The aging of the immune system ties into most other issues in aging. Immunosenescence is clearly important in Alzheimer's disease, as noted by numerous sources, as is chronic inflammation in the brain, also the subject of numerous discussions. This is also true of vascular inflammation in the brain. Loss of neurogenesis in the aging brain is partly mediated by inflammatory signaling. Inflammation drives osteoarthritis. It also involves and negatively affects the behavior of macrophage cells, disrupting their normal function, is the major cause of pituitary gland aging, and contributes to osteoporosis. Further, it harms proteostasis throughout the body. Chronic kidney disease has a bidirectional relationship with inflammatory immune aging.

When it comes to treating immunosenescence, exercise has been shown to at least modestly improve matters, as it does for most aspects of aging.

Changes in hematopoiesis, and damage to hematopoietic stem cell populations, are critical parts of immune aging. The bone marrow niche is responsible for much of these harmful changes, and chronic infection some of the rest. Researchers have considered autophagy upregulation as an approach to improving hematopoiesis. Further, CDC42 inhibition continues to look like a promising approach to improve hematopoietic function in older individuals, with more results published this year on the use of CASIN as one of the candidate drugs - it also works to promote function in other aging stem cell populations. On a related note, researchers have shown that old hematopoitic stem cells do not regain their function in a young environment, which should steer thoughts on what sort of therapies might work.

Regenerative Medicine

For tissue engineering: esearchers have built thyroid organoids that can improve function in mice; early intervention with thin cartilage sheets can turn back osteoarthritis in animal models. The research community is working towards ways to produce universal cells that can be introduced safely into any patient, thereby greatly reducing the cost of cell therapies and tissue engineering.

Cell therapies for Parkinson's disease are moving forward only slowly. Cell reprogramming is being combined with prior scaffold techniques to produce muscle tissue regeneration. Muscle stem cell populations appear largely intact in old age, just inactive. Delivery of astrocyte progenitor cells helps with stroke recovery in mice. Autologous cell therapy improves outcomes in heart failure. Interestingly, stem cell therapy improves mitochondrial quality control. Transplanted retinal cells have been shown to integrate into a damaged retina. Stem cell therapy produces tendon regeneration. Stem cell therapies might be used to treat skin aging. It is by now well known that first generation mesenchymal stem cell therapies suppress age-related inflammation, and this is under consideration as a way to treat frailty, a condition strongly associated with chronic inflammation. A clinical trial of stem cell therapy for frailty was conducted successfully this year. It is possible that the death of transplanted cells is in fact the mechanism by which inflammation is suppressed in stem cell therapies.

Exosomes derived from stem cells offer a logistically simpler approach to therapy than the delivery of stem cells themselves. Exosome treatments have been showed to work in animal models: slowing aging in progeroid mice; treating disc degeneration; producing heart tissue regeneration; acting to reduce frailty in old mice.

Cardiovascular Aging

Atherosclerosis kills a quarter of humanity via heart attack, stroke, and consequences of narrowed arteries. Preclinical atherosclerosis is widespread by age 50. At root, it is a condition caused by dysfunction in the macrophage cells responsible for clearing molecular waste from blood vessel walls. Atherosclerosis cannot yet be meaningfully reversed. Could selectively targeting the right inflammatory processes achieve that goal? Hypertension is also a contributing factor, altering arterial structure to accelerate atherosclerosis, illustrated by the point that successful control of blood pressure in later life produces a meaningful reduction in mortality. Mitochondrial dysfunction can also be argued to contribute, as can clonal hematopoiesis.

In other research into atherosclerosis and its consequences, heart attacks are more severe in sedentary individuals, and one of the consequence of a heart attack is raised harmful inflammation. Incidence of stroke is declining in later life, an outcome of the slow lengthening of life span year over year. Researchers achieved reversal of atherosclerotic plaques in mice by targeting antioxidants to the cell lysosome to clear oxidized LDL, an interesting result. Unfortunately, earlier research indicating that nattokinase supplementation can reverse plaque was not replicated in a more rigorous trial, though a lower dose was used. More work is yet needed on this topic. Hunter-gatherer populations with high levels of exercise exhibit low levels of cardiovascular disease and dementia; exercise certainly helps to reduce risk in other populations, which in turn means that a substantial fraction of cardiovascular disease is self-inflicted, the result of a sedentary lifestyle. A few other interesting research results: inflammatory macrophages contribute to the formation of aneurysms; autophagy is protective in heart aging, and perhaps a useful target for therapies to slow heart aging; adjusting the production of elastic proteins in the heart may compensate somewhat for the damage of aging.

The Human Microbiome

The gut microbiome becomes uniquely dysfunctional from person to person over the course of aging, though that process is slowed by calorie restriction. Similarly there is no one universal beneficial configuration of the microbiome. Mapping the age-related changes in the gut microbiome is an ongoing process, but still in its early stages. Does reduced tryptophan intake contribute to these age-related changes? The aging gut microbiome may contribute to age-related anabolic resistance and immune system dysfunction, and thus the onset of frailty. It may also cause problems in innate immunity. Equally, the immune system helps to garden the microbiome, and its age-related decline allows for pathological microbes to grow in number. Numerous other age-related conditions and detrimental changes are influenced by the gut microbiome, including loss of neurogenesis.

Restoration of a youthful microbiome is a field in its infancy. Fecal microbiota transplantation looks like a compelling, simple approach that may work well to restore a youthful microbiome, and thereby improve function. That includes its use as a treatment for neurodegeneration. Probiotics may also work, but there is some work yet to be accomplished in order for this to be the case. Intermittent fasting helps to beneficially alter the gut microbiome to some degree; it can reduce the contribution of the aging microbiome to hypertension, for example. Icariin supplementation improves the gut microbiome in old mice, and produces consequent health and functional benefits.

The gut microbiome recieves a lot of attention in the context of aging, but how important is the skin microbiome? That is a new question, in search of an answer. Meanwhile, the oral microbiome is thought to spread inflammation into the body via damaged gums, increasing risk of Alzheimer's disease and other conditions.

Mitochondrial Aging

There is plenty of evidence for mitochondrial aging to contribute to age related conditions. Recent research that I noted this year covered a few such conditions: sarcopenia; Alzheimer's disease (mitochondrial dysfunction in Alzheimer's is a popular topic); atrial fibrillation; and immunosenescence. Much of mitochondrial dysfunction with age may stem from a loss of mitophagy, the quality control mechanism responsible for culling damaged mitochondria. There is some question over which of mitophagy or oxidative stress is the first cause, however. Loss of mitophagy can contribute to stem cell dysfunction and the aging of the brain, among many other issues.

A variety of approaches to improving mitochondrial function, some compensatory, some not, are under consideration: inhibiting complex I activity; delivery of mitochondrially targeted peptides such as elamipretide; telomerase gene therapy; D-glyceric acid supplementation; glutathione precursor supplementation; targeting prohibitins to promote mitophagy; mitochondrial transplantation is presently a hot topic and the goal of numerous initiatives, perhaps even with the goal of transplanting entirely artificial mitochondrial-like structures; targeting the mitochondrial permeability transition pore; and upregulation of mitochondrial uncoupling, if it can be achieved in a safe way.

Cancer

I pay less attention to cancer research than I used to. I am mostly interested in approaches that can produce very broad anti-cancer therapies, those capable of being applied to most or all types of cancer without much new development per type. Reprogramming of cancer cells into normal somatic cells has been suggested as a path to cancer therapies. The most promising path to a universal cancer therapy is, I think, interference in telomere lengthening. Chimeric antigen receptor immunotherapies are performing well in comparison to the prior generation of chemotherapies and radiotherapies, but still require too much work to adapt to specific types of cancer. Nonetheless, researchers are now adding chimeric antigen receptors to immune cells other than T cells, such as natural killer cells, and making other improvements, such as triggered activation. The engineering of B cells to attack cancer cells is another, similar approach. Other approaches that caught my eye: YAP upregulation; manipulation of "don't eat me" markers abused by cancers, such as CD47; targeting TRIM28 as a way to inhibiting alternative lengthening of telomeres; finding ways to make cancer cells die rather than become senescent in response to cytotoxic therapies.

Cancer survivors have a shortened life expectancy, which may be due to an increased burden of cellular senescence as a result of cell-killing therapies.

Neurodegeneration and Damage to the Brain

There are a lot of interesting correlations in aging and neurodegeneration: visual decline correlates with Parkinson's disease, for example, as does loss of kidney function, and leakage of mitochondrial DNA into the cell cytosol. Hearing loss correlates with dementia - but also with physical impairment. Aortic stiffness correlates with cognitive decline, as does any degree of raised blood pressure. Increased activation of monocytes and macrophages appears in Alzheimer's disease patients. Gum disease correlates with neurodegenerative conditions and all-cause mortality. Reduced oxygen supply to the brain also correlates with dementia. In many cases it remains unclear as to whether causation is involved, or this is a case of underlying causes of aging producing multiple pathologies at the same time. Intriguingly, cataract surgery correlates with lower risk of dementia, which indicates that the mechanism must be that reduced sensory input due to blindness accelerates brain aging.

Neurodegeneration is linked with vascular dysfunction and reduced capillary density, a feature of aging receiving more attention these days. Amyloid may contribute to this reduction in capillary density. Loss of capillary density is in effect a hallmark of aging. The hippocampus operates at the very edge of capacity, and any reduction in the supply of oxygen and nutrients will cause loss of function. The lymphatic system of the brain is also a new point of focus in Alzheimer's disease. Separately, arterial stiffening correlates with structural damage to the brain, and particularly so in diabetic patients, as one might expect. There is an ongoing debate over whether persistent viral infections contribute to Alzheimer's disease - expect more years of this back and forth over the data. Viral proteins can assist in the spread of protein aggregates, making it more than a matter of raised inflammation.

The amyloid cascade hypothesis remains at the center of research and development for Alzheimer's disease, just as α-synuclein is central to Parkinson's disease, though a lot of effort is going into adjusting it of late. Is Alzheimer's a lifestyle disease? Perhaps, though likely not as much so as is the case for type 2 diabetes. Researchers are considering splitting Alzheimer's into four subtypes based on differences in pathology and progression. There was a sizable debate over the approval of the immunotherapy aducanumab, given the poor outcomes in patients despite effective clearance of amyloid-β. Improved approaches to this sort of immunotherapy are beneficial in animal models but will they do any better in humans? Is amyloid-β pathology due to the fact that the aggregates associated with Alzheimer's disease deplete soluble amyloid-β? Or is it that misfolded amyloid-β spreads within cells, and the aggregates outside cells are less important? Amyloid-β aggregation can degrade synaptic connections. Does the amyloidosis of Alzheimer's disease actually start in the liver in some cases, in the same way as Parkinson's synucleinopathy can start in the intestinal tissues? Researchers are now suggesting that there is a tipping point in amyloid-β aggregation after which Alzheimer's is inevitable.

Loss of myelin maintenance is important in cognitive decline, as is blood-brain barrier dysfunction, allowing harmful cells into the brain. The supporting glial cells of the brain can both help and harm the blood-brain barrier in aging. Cholesterol metabolism might be important in Alzheimer's disease, but exactly how this is the case is up for debate. A great deal of evidence points to microglial dysfunction in the development of neurodegenerative conditions; these cells become more inflammatory with age, but also lose beneficial functions. They may also be important in the spread of tau aggregates. This may be aggravated by persistent viral infection. In synucleinopathies, α-synuclein pathology may be spread via lysosomal transfer between glial cells.

Assays for the early stages of neurodegenerative conditions will likely soon improve greatly. Detecting misfolded amyloid-β in blood, for example. Functioning of the glymphatic system in clearing molecular waste from the brain is coming to be seen as important in brain aging.

When it comes to discussion of therapies: tau knockdown gene therapy does well in mice, and tau immunotherapy is so far performing somewhat better in human patients than is the case for amyloid immunotherapy; telomerase gene therapy has seen one small trial, and awaits more; B cell depletion produces benefits in Alzheimer's mouse models; similarly clearance of microglia appears beneficial, as does CD22 inhibition to improve the behavior of microglia; adding new photosensitive proteins to the retina to replace the function of lost photoreceptor cells; delivery of klotho is neuroprotective; ultrasound treatment can improve mouse memory; a plagl2 / dyrk1a gene therapy restored youthful neurogenesis in mice; amyloid-clearing immunotherapies continue to be a major focus of the clinical development community even though they are failing to improve patient outcomes following successful clearance; chondroitin 6-sulphate gene therapy restored memory function in old mice; transcranial direct current stimulation has the most consistent evidence of the many approaches to electromagnetic stimulation of the brain.

Lastly, exercise does help to improve function and slow neurodegeneration, a conclusion based on extensive data. Since exercise is essentially free, even modest results are cost-effective. Recent research suggests, however, that in mice at least there is a narrow therapeutic window for exercise to improve neurogenesis. This doesn't conform to the broader findings of increased neurogenesis and benefits to function, so it will be interesting to see how this area of research proceeds. As a final thought, some high functioning older people retain good memory and functional connections in the aging brain. Why? More work is needed on this topic.

Other Age-Related Molecular Waste

Much of the world on amyloid is focused on amyloid-β and Alzheimer's disease, but there are numerous other sorts of amyloid in the aging body. Treatment of transthyretin amyloidosis is a going concern these days, though there is definitely room for improvement on the first therapies that focus more on destabilizing the problematic transthyretin forms than on actively removing them. Transthyretin amyloidosis contributes to numerous issues in aging, with growing evidence for it to be important in heart disease. in other news, amyloid contributes to muscle aging. Transient AGEs are important in the chronic inflammation attendant to metabolic diseases such as diabetes because they trigger the receptor RAGE and consequent inflammatory signaling. This can contribute to disc degeneration.

Epigenetics and Cellular Reprogramming

Epigenetic changes in aging are a hot topic these days, particularly since the rise of partial reprogramming as a way to reset epigenetic changes characteristic of aging. The present consensus is that this is a promising path to therapies to treat aging and age-related degeneration. Reprogramming is the adaptation of the process that naturally takes place during embryogenesis to clear out damage and form the embryonic stem cells that give rise to a young body. One important unanswered question is whether the epigenetic reset can be separated from dedifferentiation into stem cells; it is highly desirable to only achieve the former of those two outcomes. Reprogramming has slowed aging in progeroid mice, and was also shown to improve muscle regeneration. A range of other interesting demonstrations have been produced in recent years, such as regeneration of damaged heart muscle.

Many different projects, some with sizable funding, are attempting to build rejuvenation therapies based on reprogramming. If the cancer risk can be controlled, this could be a beneficial therapy for older people. There is clearly a great deal of work ahead in moving from early animal studies to widespread clinical use, and many challenges to solve. Related to the concept of reprogramming is the idea of introducing developmental signaling into adults in order to spur greater regeneration, an approach still at an early stage.

Work on epigenetic clocks continues apace, with the number of different clocks expanding rapidly. Some researchers argue that more attention should be given to traditional measures of frailty. For preference, more of this effort and funding directed to the relentless development of new clocks should be directed towards validating and understanding the clocks that exist. Understanding how age-related damage and dysfunction maps to specific epigenetic changes is important. It will be hard to use the clocks to assess therapies without that, and there are already too many studies publishing clock data with no accompanying health data, a trend that is detrimental to progress. Elsewhere, researchers proposed the basis for a universal mammalian clock. The GrimAge clock continues to produce good results to show it is much improved over earlier clocks. Cardiovascular health correlate with a lesser epigenetic age acceleration as measured by clocks. Epigenetic age acceleration also correlates with loss of kidney function.

Diet and exercise can be used to reduce epigenetic age by a few years, and the effects of diet are distinct from those of exercise. Heterochronic parabiosis also reduces epigenetic age in mice. Lastly, epigenetic clocks are being used with some success to establish chronological age in species where that is challenging via other means, such as lobsters.

Fasting and Calorie Restriction

Intermittent fasting as a way to modestly slow the progression of aging is a popular topic these days, and more rigor is being applied to testing fasting as a form of therapy. For Parkinson's disease, for example. Short term fasting can improve numerous measures of immune function, and this is a basis for its use in cancer patients. There is some work underway to directly compare the results of intermittent fasting versus calorie restriction in humans, an exercise long overdue. Researchers are questioning the once-daily feeding pattern in mouse studies of calorie restriction, suggesting that it may be allowing fasting-like mechanisms to operate significantly. On a related note, dogs have been found to benefit from time-restricted feeding.

That aside, calorie restriction is well known to slow aging in numerous species, and every year the research community produces more examples of specific manifestations of aging that are beneficially affected by a lower calorie intake. Calorie restriction slows cognitive decline, muscle atrophy, and lowers blood pressure and cardiovascular disease risk. Calorie restriction is proposed as an adjuvant therapy for cancer patients, and may impact cancer and cancer risk through reduced growth signaling. Calorie restriction is better than intermittent fasting at slowing cancer in mice. Methionine restriction, triggering just one of the nutrient sensing pathways, improves cognitive function in mice. It also improves the microenvironment of the aging brain. Calorie restriction slows renal artery aging. It also improves stem cell function.

An intriguing question: how much of the benefit of a healthy, non-restricted diet is due to the effects of natural calorie restriction mimetic compounds? This could be answered by suitable studies, but that work has yet to be done. In general, calorie restriction mimetic compounds assessed to date compare poorly to the practice of calorie restriction.

Parabiosis and Plasma Dilution

Plasma dilution emerged from parabiosis studies, is being tested in formal and informal trials, and there is some reason to think that it may be worth persuing as a modestly effective way to reduce the impact of aging on inflammatory signaling and other aspects of metabolism. That said, there is evidence to suggest that it isn't the dilution, but rather the albumin that must be provided when blood is diluted. Meanwhile, work on parabiosis itself continues apace, as does work on transfusion based therapies. Researchers have found that transfusions from fit mice to sedentary mice produce benefits to health, in large part mediated by clusterin levels, while serum from young mice improves muscle regeneration in old mice.

Self Experimentation

This year, I published some results from a self-experiment with flagellin immunization to adjust the gut microbiome, and a protocol for running a self-experiment with Khavinson peptides for thymic regrowth. In other news, a paper was recently published on a self-experiment with a growth hormone releasing hormone gene therapy; adventurous and risky, given the side-effects of upregulating growth hormone. It makes for an interest read, given that reducing growth hormone is the common strategy to slow aging and extend life in animal studies.

Short Essays

I write short essay posts here at Fight Aging! less often than I used to; the pressures of time loom large. Here are a few from the past year, however.

• Request for Startups in the Rejuvenation Biotechnology Space, 2021 Edition
• In the Best of Plausible Futures, We Will All Be Occasional Cancer Patients
• Wanted: A Non-Profit to Run as Many Low-Cost Trials of Promising Treatments for Aging as Possible

Odds and Ends

As ever, some items resist easy categorization, but are nonetheless interesting enough to mention. There is prehaps less agreement on a definition of aging than one might think. The children of the 21st century will largely live to be 100 or more if present longevity trends continue, despite the fact that 7.2% of the world's deaths can be attributed to the spread of sedentary lifestyles, and little further gain in human life span is possible via environmental improvement. Yet we should remember that 95% of present centenarians are frail: rejuvenation therapies are much needed. The correlation between wealth and longevity likely does not have cultural or genetic causes.

Radiation hormesis continues to be a topic of interest. Does gum disease speed other aspects of aging via inflammation, as thought, or by oxidative stress, as recently proposed? Historical gains in life expectancy were not just a matter of reduced child mortality, but occurred at all ages. Only a subset of cells in visceral fat are responsible for the harms that it causes to health and metabolism. Age-related vision impairment correlates with all cause mortality in later life. There is a growing portfolio of projects targeting myostatin as a basis for muscle growth. That fullerenes might extend life in mammals has quite comprehensively failed to replicate, as many of us expected would be the case. Some researchers are working on a gene therapy platform specifically for skin rejuvenation. The Hallmarks of Aging are now so ubiquitous in the literature that it is possible to find people willing to critique them rather than just cite them.

ENH1 inhibition allows scarless healing of skin injuries in mice. Flies raised in a germ-free environment have some aspects of aging slowed. Disruption of elastin structures in skin is a big problem, as there is no good approach queued up at an advanced stage of research. It will likely require carefully programmed cells in order to produce the right structures for youthful function. Telomerase and follistatin gene therapies extend life in mice. Most small molecules shown to slow aging change the expression of extracellular matrix genes; is there anything to be learned from this? VEFG gene therapy slows the loss of capillary density and extends life in mice, which is interesting given that one might expect this to produce damaged vessels, as that is what happens in wet macular degeneration in the retina. Ribosomal improvements lower errors in protein synthesis and modestly extend life in short-lived species.

There is continued progress towards reversible cryopreservation of organs, and on balance cryopreservation has a bright future - the question is how long it will take for that future to arrive.

While it is worth remembering that the demographic data on aging at very advanced ages is shaky at best, any number of novel views and models of aging are being put forward these day: the role of rate-limiting processes; a proposed staging system for aging in the clinic; aging as an emergent phenomenon; borrowing particle physics concepts to model aging; the tumor suppressor theory of aging; the adaptive-hitchhike model of the evolution of long-lived species; aging as a consequence of the colonization of land; a tripartite view of aging; the evolutionary layering of the hallmarks of aging; that compression of morbidity is in part the result of a failure to adequately treat the oldest people; the importance of the exponential mortality curve and what it tells us about aging; half of the gains in longevity since the 1960s are the result of technological progress rather than public health measures such as suppression of smoking; the expectation that the upward trend in life expectancy will increase in the future. Is thinking of aging as a contagious process in the body a good model for the way in which failing systems interact? Lastly, the hyperfunction theory of aging remains an at times confusing model, in need of clarification from those who argue for it.

Last Thoughts

People sometimes ask me why I am enthused by senolytics, and very bullish on accelerating the path to further trials and widespread use of the existing senolytic treatments like the dasatinib and quercetin combination. Just take a look at the year of references earlier in this post, linking senescent cells to pathology and their clearance to reversal of that pathology, dozens of papers and studies that I just happened to notice in passing this year. Or look at a similar wall of links to promising results from the end of last year. They are by no means comprehesive lists, only the work that caught my eye. The clearance of senescent cells produces results in animal studies that are far and away superior to any other approach tried to date when it comes to the rapid reversal of age-related disease.