While I suspect that COVID-19 will feature prominently in most retrospectives on 2020, I'll say only a little on it. The data on mortality by year end, if taken at face value, continues to suggest that the outcome will fall at the higher end of the early estimates of a pandemic three to six times worse than a bad influenza year, ten times worse than a normal influenza year. The people who die are near entirely the old, the co-morbid, and the immunocompromised. They die because they are suffering the damage and dysfunction of aging. Yet the societal conversation and the actions of policy makers ignore this.
There is little discussion outside the research community on greater efforts to restore immune function in the old, or indeed about the reality of the age-related mortality of COVID-19 at all. All infections are treated as equally dangerous; the media dwells extensively upon the very few young victims; the whole of society is closed, at staggering cost, when the risk to most of society is little worse than yearly influenza, and certainly less than that of than driving to work. There was a better approach to this, a cloistering in safety for only the vulnerable, and a continuing willful blindness to that better approach. A cynic might argue that those factions among the powers that be that are ever seeking after greater control, greater surveillance, greater submission, greater conformance, are in the driver's seat these days.
This issue with COVID-19 and aging is perhaps a subset of the broader collection of mistaken views on aging, some of them actively propagated by researchers. Take the concept of "successful aging" for example. By definition, age is an increased risk of death and disease. That is not success, and even where people are using this term to mean a slowing of decline, that is simply aiming too low. We can do better. Rejuvenation is possible in principle, via periodic repair of underlying damage. This has been demonstrated in animal models via strategies such as clearance of senescent cells, and should be the primary goal of research and clinical development.
The Longevity Community
Philanthropic fundraising for research has been impacted by the pandemic, like many other areas. The SENS Research Foundation is nonetheless still running their year end fundraiser, with nearly a million dollars in matching funds from generous donors as an incentive. Donate before the year ends! Further, COVID-19 is no barrier to ongoing conversations, education, and persuasion, whether Aubrey de Grey talking to the Effective Altruism community, the SENS Research Foundation putting out their annual report, or continued political advocacy for longevity in Europe, where single-issue political parties are a viable approach. Much of the world has yet to be persuaded that the treatment of aging is possible, something other than a pipe dream. There is work to accomplish, eyes to be opened.
The longevity industry has been relatively insulated from the impact of COVID-19, which is to say progress has been slowed, but not derailed. Setting aside the dramatic reduction in biotech investment for much of 2020, the usual investor reaction to panic and uncertainty, most life science companies are classed as essential businesses in the US and have continued to work through the shutdown. The more advanced of the early companies have treatments in clinical trials, even while most are still at the preclinical stage. New companies have launched, though we still need many more to cover areas yet to be worked on in earnest. Existing companies made progress and raised funding throughout the year: covered Juvena Therapeutics, Senisca, SIWA Therapeutics, Calico, Oisin Biotechnologies and OncoSenX, the other senolytics companies as a whole, Kimer Med, Insilico Medicine, Five Alarm Bio and Biosens, OneSkin's DNA methylation clock for skin aging, Lygenesis, Juvenescence (several times), Turn.bio and other Methuselah Fund porfolio companies.
EnClear Therapies brought in $10 million for their approach to cerebrospinal fluid filtration to remove molecular wastes that contribute to neurodegeneration. Revel Pharmaceuticals finally obtained seed funding to work on glucosepane cross-link breakers. BioAge raised $90 million for clinical trials of small molecules to slow aging. Investors are building funds and other vehicles (such as the Moonshot Venture Fellowship) to focus on the longevity industry. Examples include Ronjon Nag, Kingsley Advani, and the folk at SP8CEVC, Longevitytech.fund, and LongeVC. It nonetheless remains the case that there are too few experienced biotech funds involved able to support later, larger investments. That is changing, slowly.
Some initial clinical trials have been failing, as often takes place in the early years of an industry. Unity Biotechnology's first senolytic failed phase 2 trial for knee osteoarthritis, provoking a great deal of discussion (some justified, some unfairly post-hoc) as to why it was a poor design and strategy. Still, Big Pharma entities are starting to launch their own senolytics programs. There is gold in those hills.
Conferences of Interest
I attended a few conferences in person in early 2020, prior to the COVID-19 shutdowns, and wrote up notes. The SENS Research Foundation pitch day during the J.P. Morgan Healthcare conference offered a most interesting selection of startups from the longevity industry. Much the same could be said of the Longevity Therapeutics conference, with the addition of researchers presenting on their academic programs. It was all online conferences after that, however. Later in the year I noted a selection of senolytic company showcases from the Longevity Leaders event, and some of the panels from Longevity Week events.
Senescent Cells and Senolytic Therapies
The development of senolytic drugs to clear senescent cells, as well as methods of assessing their effectiveness, is rolling onwards, broadening to include many novel strategies, and attracting greater attention from beyond the scientific community. Further data arrived this year to support the use of senolytics to expand the donor organ supply by salvaging otherwise unusuable organs. Additionally, studies have shown or suggested that senolytics can treat a very wide selection of conditions: osteoporosis, cardiovascular disease, the chondrocyte hypertrophy characteristic of osteoarthritis, osteoarthritis more generally, vulnerability to the cytokine storm of SARS-CoV-2 infection, fibrotic disease, atrial fibrillation, a range of other heart issues, peripheral neuropathy caused by chemotherapy, Alzheimer's disease (a fair amount of research here) and other neurodegenerative conditions, pulmonary fibrosis, glaucoma and other eye conditions, non-healing wounds, even when caused by diabetes, chronic kidney disease, loss of insulin sensitivity, cancers of bone marrow, cervical cancer, accelerated aging resulting from cancer treatments, the atrophy of the thymus, and lung disease. Demonstrating that nothing is ever universally true in biology, researchers found this year that uterine fibrosis does not respond to senolytic treatment, unlike the other forms of fibrotic disease tested.
This year OneSkin launched their topical senolytic treatment, ahead of any published data on its effectiveness in humans, though the data in skin models is intriguing. Of other new approaches to senolytics, taking existing cell-killing drugs and making them safe prodrugs - only activated in the target cells, rather than generally - is perhaps most interesting. Conjugating navitoclax with galactose, for example, ensuring that it is only cleaved into the cytotoxic navitoclax in senescent cells. That has also been accomplished for other chemotherapeutics. Another evolution of navitoclax to reduce its harmful side-effects is to turn it into a PROTAC drug, a compound that removes target molecules by causing them to be degraded by the ubiquitin-proteasome system.
Vaccination against CD153 appears to be mildly senolytic, as are SYK inhibitors, through an as yet unknown mechanism of action. Researchers are still attempting to determine whether nutraceutical senolytics (including plant extracts such as fisetin or the senotherapeutic naringenin) can be effective enough to be interesting. In most cases, one suspects not. MYSM1 upregulation reduces the senescent cell burden in mice. Chimeric antigen receptor approaches can be used to produce senolytic immunotherapies, though not particularly cost-effective ones. Physical fitness, on the other hand, reduces inflammation, but isn't senolytic at all. Reversing cellular senescence by delivering new mitochondria or PDK1 inhibition is scientifically interesting, but sounds risky - some fraction of senescent cells are damaged in ways that may lead to cancer. Hormone therapy in women correlates with lower SASP expression, though it is unclear as to why this is the case. Researchers have started to examine the past use of long-approved drugs newly found to be senolytic, to see if there is any evidence for the degree of benefits. So far this is proving to be challenging.
Beyond senolytics, researchers continue to mine the biology of senescent cells in ever more depth. Any mechanism involved in the onset or maintenance of senescence might turn out to be a useful basis for therapies. The SASP Atlas is one of the results of this work, mapping the senescence assocatiated secretory phenotype (SASP), potentially a rich source of ways to measure the burden of senescence. TGF-β is an important SASP component implicated in the transmission of senescence via the SASP, and so may be microRNAs miR-21 and miR-217. The SASP component CyPA may link hematopoietic cell senescence with cognitive decline. Some degree of suppression of the SASP can be achieved via a variety of approaches, including HDAC inhibition and inhibition of ATM kinase. G3BP1 is required for the SASP to exist, making it perhaps a more attractive potential point of intervention. Genetic databases are being used to identify genes involved in inhibition of cellular senescence - targeting those genes may be a basis for therapy. The genomic architecture of senescent cells is quite different from that of normal cells, and the details are being mapped in more detail. It is possible that non-replicating cells develop a senescence-like state in aged tissues.
Further research is ongoing. Astrocyte senescence kills neurons in cell culture, implicating these cells in neurodegenerative conditions. A better understanding has been developed of how senescent cells cause lung fibrosis (the target of one of the clinical trials for senolytic drugs). USP7 inhibition was shown to be senolytic. Vascular cellular senescence is increased by microRNA-34a. It is suggested that variability in outcomes in stem cell transplantation may be due to the presence of more or fewer senescent cells after expansion of the cells for transplant. Senescent cells contribute to declining NAD+ levels in aging.
Tissue by tissue data is finally arriving for senescent cell accumulation, for both mice and humans. A taxonomy of senescence is beginning to form, as researches start to get a handle on how senescence can differ between cells. A senescent population for which removal might be problematic was identified in the livers of aged mice. Researchers are exploring roles for long non-coding RNAs in cellular senescence. Persistent CMV infection provokes greater senescent cell accumulation, perhaps by causing immune dysfunction. AQP1 is involved in cellular senescence in tendons. Senescent cell accumulation may also be the primary mechanism by which cosmic radiation exposure produces detrimental health outcomes. T cell senescence increases with age and is quite harmful, forming part of an inflammatory feedback loop that can damage healthy tissue.
Some researchers argue that cross-linking is a hallmark of aging that was overlooked by the authors of the noted Hallmarks of Aging paper. Stiffening of the extracellular matrix in tissues is a consequence of cross-linking, among other factors, is normally considered in skin and blood vessels, but researchers noted this year that it contributes to age-related loss of muscle function as well. A novel approach to breaking cross-links was discussed, the use of spiroligomers, carefully designed to interact in specific ways with cross-link molecules. The supporting work needed for projects focused on glucosepane cross-links, the most prevalent in humans, continued this year with the creation of anti-glucosepane antibodies. Researchers have also proposed inhibition of protein glycation as a way to reduce the creation of cross-links, though life-long therapy of this sort compares unfavorably with approaches that can be applied every few years to clean up existing cross-links. Measuring the cross-link burden in tissues remains challenging; more work will be needed here as targeted approaches to remove cross-links become viable.
There are many forms of amyloid, misfolded proteins that replicate and aggregate in the body, beyond the few (amyloid-β, tau, α-synuclein) that are the focus of neurodegenerative research. This year, it was noted that medin amyloid causes cerebral vascular dysfunction. A good overview of transthyretin amyloidosis was alo published recently.
Microbiomes and Aging
The microbiomes of the body, particularly that of the gut, and their relationships with age are an area of growing research interest. Age-related changes in microbial populations take place, both caused by mechanisms of aging and causative of age-related dysfunctions, a two-way relationship. While most research focuses on the gut microbiome, the skin microbiome was given more attention of late, as are the varied microbiomes of the rest of the body. Researchers are in the process of cataloging specific gut microbial metabolites that harm or aid the body, and for which production changes with age: butyrate is beneficial, while trimethylamine is harmful to arterial function. Polyamine from gut microbes may mediate the relationship between higher environmental temperature and lower rates of osteoporosis. In general, aging results in larger inflammatory populations of gut microbes, and inflammation may be the primary way by which changes in the gut microbiome contribute to conditions such as Alzheimer's disease. In that context it is interesting that changing metabolite production by the microbiome correlates with amyloid burden in the brain. Transplanting gut microbes from old mice to young mice impairs cognitive function.
When it comes to addressing age-related changes in the gut microbiome, a wide range of strategies are being discovered and refined. Supplementation with IAP reduces gut inflammation. Delivery of cyclic peptides suppresses harmful populations to much the same end. Transplanting gut microbes from old rats to young rats produces inflammation and cognitive decline. The old standby of programs of physical activity may exert some of its beneficial effects on health via better maintenance of the gut microbiome.
Immune Aging and Chronic Inflammation
The immune system declines with age, in a complex and yet to be fully mapped fashion. Thus building better vaccines for older people is a poor alternative to rejuvenation of the immune system. We shouldn't need COVID-19 as a reminder in order to be able to argue for greater research into immune system rejuvenation. Yet a lot more work takes place on improving vaccines than there is on improving the immune system, more is the pity.
Immune aging isn't just the cause of increased mortality due to infectious disease. It is likely a major driver of many age-related conditions via chronic inflammation, the persistent unresolved activation of the immune response. This and other issues ensure that rejuvenation of immune function is vital to the treatment of aging. Sustained inflammation encourages cancer metastasis, and the progression of many other age-related conditions, including sarcopenia, vascular stiffness, and, ironically, dysfunction in the generation of new immune cells. It harms the blood-brain barrier, enabling the passage of damaging molecules and cells into the brain. In the brain, microglia become ever more inflammatory with age. It is thought that the evolutionary tradeoff that has produced this inflammatory aging of the immune system is between (a) protection against infection via greater immune activation versus (b) faster aging due to that immune activation.
Inflammation manifests in the actions of the immune system, but has its source in forms of molecular damage and cellular dysfunction in tissues throughout the body that provoke those actions. It is the failure of the immune system to clear senescent cells in later life that accounts for a great deal of that provocation. Skin tissue, being the largest organ provides a sizable contribution, but perhaps not as much as visceral fat tissue in overweight individuals, both tissues becoming laden with senescent cells in older people. Gum disease is another common contribution to raised inflammation, and a risk factor for inflammatory age-related conditions. Cortisol levels decline with age, causing macrophages to become more inflammatory. Interestingly, some contributions to chronic inflammation are physical and structural, such as shear stress in the blood flow of the heart.
Suppression of inflammation by interfering in cell signaling is a going concern, but present clinical strategies are blunt tools. The research community in search of more sophisticated ways to achieve this goal, only suppressing undesirable, excessive, long-term inflammation, while allowing useful, short-term inflammatory processes to proceed. The NLRP3 inflammasome is one potential target. The small molecule MW189 has been tested in patients to reduce inflammation in the brain. IGF-1R inhibition reduces inflammation in Alzheimer's disease mouse models, and delivery of BDNF reverses inflammatory microgial activity in the brains of old mice. MicroRNA-192 in extracellular vesicles suppresses inflammation, and so is a potential basis for treatments. Metformin can reduce liver inflammation. Glucosamine supplementation and TNFα blockade may reduce mortality by lowering inflammation. Alpha-ketogluarate may do much the same. The ketone body β-hydroxybutyrate and RAGE inhibition also inhibit inflammation. Eosinophil immune cells are anti-inflammatory and decline in number with age. Delivering eosinophil cells into visceral fat reduces chronic inflammation caused by that tissue.
The thymus atrophies with age, and evidence continues to accumulate to show this to be an important contributing cause of immune system decline. The thymus is where thymocytes, created in the bone marrow, go to become T cells of the adaptive immune system. Fewer new T cells means a growing loss of immune function. So why not rebuild a thymus? Recellularizing a rat thymus with human cells produces a functional thymus, only the latest of a range of tissue engineering approaches. Thymic atrophy is in part caused by loss of function in thymic epithelial progenitor cells. Cell therapy approaches to thymic regeneration are possible, and two were demonstrated in animal models this year using reprogrammed embryonic fibroblasts and T cell progenitors.
Other approaches exist - and are necessary - to address immune system aging. Replacing the hematopoietic stem cell population for example, as it becomes damaged and dysfunctional, or at the very least stop the signaling that degrades hematopoiesis. Introducing young hematopoietic stem cells extends life span while transplanting bone marrow improves measures of aging, both in old mice. Pharmacological approaches to improving the existing population are more widely considered, however.
Genetics of Aging
The study of genetic variants and their role on longevity is increasing looking like a dead end from the point of view of discovering ways to meaningfully slow or reverse aging. Intensive and expanding analysis of data has found very few genetic influences on longevity, and the effect sizes are small. There are still those who think that very rare variants with large effects on longevity could exist, buried somewhere in the human data. The business as usual is still a matter of discovering variants with small effects on mechanisms connected to aging, however. A BPIFB4 variant affects inflammation and is found in long lived individuals. Overall, long-lived humans do not exihibit fewer harmful gene variants, perhaps suggesting that genetics has a small effect only on variations in life expectancy.
Nuclear DNA damage of various types occurs progressively with age, and is certainly a cause of cancer. Beyond cancer, researchers are investigating the clonal expansion of mutations that occur in stem cells and progenitor cells in order to find out whether it contributes meaningfully to metabolic disarray in aging. This may or may not be the case, and isn't the only possible mechanism by which further harm may occur. An abnormal chromosome count, aneuploidy, is another form of damage, though it is argued that this can be beneficial in some circumstances, an adaptation that tries to resist some of the damage of aging. Repetitive elements that can copy themselves in the genome are yet another form of DNA damage. They are suppressed in youth, less so in old age. This can be used as the basis for a biomarker of aging, as illustrated by the fact that repetitive element activity is reduced by many interventions known to slow aging in mice.
Mitochondrial function declines with age, and disruption to mitochondrial structure and activities is noted in many specific age-related conditions, such as cardiovascular disease in general and heart failure and atherosclerosis specifically. Loss of mitochondrial function in T cells produces accelerate aging symptoms in mice. That same loss in monocytes contributes to chronic inflammation in aging. Low mitochondrial DNA copy number was shown this year to produce age-related epigenetic changes in the cell nucleus.
Heart issues are connected to failing mitophagy, the quality control mechanism responsible for removing worn and damage mitochondria, and which falters in its operation with age. Loss of mitophagy is implicated in many age-related conditions, and upregulation of mitophagy is considered a good basis for therapies to improve age-related conditions. Some of this age-related decline in mitophagy is proximately caused by epigenetic changes that suppress mitochondrial function, while deeper causes remain debated.
Many groups are trying to find ways to slow or at least somewhat reverse mitochondrial decline with age. Mitochondrially targeted antioxidants have made their way into the supplement market, or clinical trials and approval in some countries. It remains to be seen how they compare with exercise or NAD+ enhancement. SS-31 is an example yet to reach the clinic, still gathering data. Other approaches include downregulation of miR-155-5p, and delivery of whole new mitochondria to replace the old ones, shown to improve function in old mice. Photobiomodulation via near infrared light appears to modestly improve mitochondrial function, and visual function in older people, though how it does so remains to be determined. Long term low dose ethanol intake extends life modestly in mice and is suggested to do fo via improved mitochondrial function.
Among the better approaches to mitochondrial aging under development, the SENS Research Foundation is one of the few groups presently working on alloptic expression. This is the copying of mitochondrial genes into the cell nucleus in order to avoid the negative consequences of mitochondrial DNA damage. At present the consensus on the cause of mitochondrial DNA damage is learning towards it occuring during DNA replication rather than by interaction with reactive molecules. Not that all mitochondrial DNA damage is equal, as point mutations are well tolerated. It is more disruptive mutational damage that causes issues. Repair of that damage - or potentially allotopic expression to make the damage irrelevant - is a potential treatment for the aging of the heart.
NAD+ levels decline with age, and NAD+ upregulation improves mitophagy and mitochondrial function. For example, it reduces the burden of point mutations in mitochondrial DNA and slows female reproductive aging in mice. Loss of NAD+ is implicated in circadian rhythm dysfunction. There are many approaches to NAD+ upregulation, some dating back through decades of sporadic clinical trials, and none of which have yet been shown to increase NAD+ any more than is the case for structured exercise programs. This year saw new data for nicotinamide mononucleotide supplementation to improve neurovascular function and fertility in mice. Animal data on nicotinamide riboside supplementation also continues to be published: it improves the generation of immune cells in mice. Additionally, CD38 is becoming a target of interest related to NAD+ metabolism due to is role in degrading NAD, but it is a little early to say what sort of therapies might emerge to target CD38.
There is some debate over whether age-related hearing loss is caused by damage to sensory hair cells or via loss of the connections between those cells and the brain. Chronic inflammation is shown to be a significant factor in the risk and development of age-related hearing loss, as is loss of mitochondrial function. Hearing loss may contribute to the onset of dementia by depriving the brain of stimulation necessary for normal operation.
Blood Vessels and Blood Pressure
A reduction in the capacity to grow new blood vessels, and consequent loss of blood vessel density, takes place throughout the body with age, reducing blood supply, with negative consequences that are most noticable in energy-hungry tissues such as the brain, muscles, and especially the heart. It is noted that a better blood supply to the brain slows cognitive decline with age. Exercise can increase blood vessel density, at least in mice. Other approaches to achieve this goal presently under study focus on BMP6 and VEGF-B.
Raised blood pressure, hypertension, is one of the more harmful downstream consequences of the underlying molecular damage of aging. It causes structural damage to tissues, and aggressive control of blood pressure - without addressing the causes of hypertension - can rein in further downstream harm such as damage to the brain that accelerates cognitive decline. Indeed, early control of hypertension in later life reduces risk of dementia and atrial fibrillation. More intensive blood pressure reductions lead to a few year increase in life expectancy. This increase holds even in the most frail of elderly people. Further, gene variants associated with risk of hypertension also associate with reduced life expectancy.
Atherosclerosis is probably the worst thing to happen to blood vessels with age, in that it kills a sizable fraction of the population. By the time they are in their 40s, many people already have preclinical atherosclerosis, a study revealed this year. Atherosclerosis is driven by inflammation, and reducing chronic inflammation is as effective as lowering blood cholesterol in the treatment of the condition. There are numerous ways in which macrophages might be manipulated to slow or reverse atherosclerosis, given their role in clearing up damage to blood vessel walls. Some approaches published this past year include adjusting their polarization or encouraging them to greater clearance of debris in atherosclerotic plaque. Other approaches don't directly target macrophages, but do benefit them, such as cyclodextrin-containing nanoparticles that sequester harmful oxidized cholesterol. CD9 blockade appears to prevent senescence in endothelial cells, and was demonstrated to reduce progression of atherosclerosis in mice.
Heterochronic parabiosis is the joining of two circulatory systems, an old and young animal. The young animal exhibits signs of accelerated aging, while the old animal exhibits signs of rejuvenation. Research initially focused on potential factors in young blood that might be producing benefits. Now however, evidence continues to emerge for the dilution of harmful factors in old blood to be the primary cause of benefits resulting from parabiosis. A few months ago, researchers demonstrated that plasma diluation reduces inflammation and improves cognitive function in old mice, and shortly thereafter self-experimenters ran a small human test based on this work, with intriguing signs of benefits.
The regenerative medicine community is focused on cell therapies to provoke greater regeneration, largely through signals secreted by the transplanted cells, rather than any significant integration of those cells. This is an area of research and development too large to do more than point out a few highlights and reviews, such as a discussion of the present state of mesenchymal stem cell therapies, reversal of photoaging via stem cell transplantation, or replacement of microglia or dopaminergenic neurons in the brain. Reprogramming is an interesting topic, when used to produce, say, patient-matched photoreceptor cells for transplantation to treat retinal degeneration, or neurons for transplantation as a stroke treatment. Reprogramming has of late been delivered in vivo, changing cells in living animals. This has been shown to improve cognitive function.
A great many stem cell therapies can in principle be replaced with the delivery of extracellular vesicles secreted by those stem cells. This is logistically easier to take to the clinic, is as effective where compared head to head, and thus an area of considerable activity at the moment. Examples of the potential of this approach are accumulating: stroke recovery via neural stem cell exosomes; a treatment for neurodegenerative conditions; a treatment for sarcopenia; a treatment of skin aging; a way to suppress senescent cell signaling.
Further, many regenerative therapies might in principle be replaced with treatments that restore native stem cell activity, which declines with age, or due to chronic inflammation. This is at least the case in people whose stem cell populations are not very damaged by aging. Such potential therapies are largely based on manipulation of cell signaling, such as Wnt signaling. A variety of such approaches were reviewed in the context of restoring muscle stem cell activity, a population known to largely retain its capabilities into later life, even while becoming quiescent. Secreted stem cell factors are proposed as a treatment for male pattern baldness. Lin28 upregulation and electrical stimulation can spur nerve regeneration. Lef1 upregulation enables skin regeneration without scarring, while protrudin gene therapy provokes regeneration in optive nerve.
There are other approaches, such as the guide nerve regrowth or heart tissue regrowth that would not normally have occurred. More cells survive for longer following transplantation if supported by a scaffold such as a heart patch, or if treated before transplantion with strategies such as mitochondrial transfer. Decellularization is another approach, using donor organs stripped of their cells. This can be done between species, as demonstrated by the production of tiny human livers from decellularized rat livers. Other unrelated work includes improving transplanted stem cell function via tethered signal molecules, improving mitochondrial function in neurons to cause greater regrowth, or using small bioprinters to print structured tissue directly into wounds.
Neurodegeneration is a blend of many forms of damage and symptoms, not nice neat categories of disease. This is another area in which a great deal of work takes place, making any selection of that research something of a sampler plate. The risk of dementia is falling for any given individual, but total incidence is increasing because the population is increasingly older. The integrity of the blood-brain barrier declines with age, allowing harmful molecules and cells into the brain, where they can cause issues such as chronic inflammation. Other forms of vascular dysfunction also contribute, and are often reviewed in the literature. Inflammation due to the aging of the immune system is very much associated with neurodegenerative conditions such as Alzheimer's disease. Targeting mechanisms of inflammation to suppress it in brain tissue is considered a basis for the development of therapies, and is shown to slow the onset of neurodegeneration in animal models. Additionally, the presence of bacterial DNA appears to promote tau aggregation through mechanisms independent of the inflammation of infection. Persistent infection is hypothesized to contribute to Alzheimer's disease.
Mitochondrial decline led by a progressive disruption of the quality control mechanism of mitophagy are implicated in numerous neurodegenerative conditions. Impairment of the ubiquitin-proteasome system responsible for recycling proteins also appears relevant. Loss of myelin seems to have some negative effect in aging, as illustrated by the connection between declining oligodendrocyte production and failing memory, oligodendrocytes being the cells responsible for maintaining myelin. Thus it is interesting to note potential strategies to spur greater remyelination, such as PAR1 inhibition, theophylline use, and glial progenitor cell therapy. Researchers are looking for ways to improve mitochondrial function in neurons, to reverse the age-related loss that is linked to neurodegeneration. Activating ILC2 immune cells results in signaling that improves cognitive function, involving IL-5 and other yet to be identified molecules. HDAC1 activation improves DNA repair in neurons and slows cognitive decline. PTB inhibition converts astrocytes into neurons, reversing Parkinson's symptoms in mice. A fisetin variant, CMS121, has slowed disease progress in Alzheimer's mice. Parkinson's disease is splitting into two distinct conditions that converge on the same outcome. ISRIB treatment in old mice quickly restored youthful cognitive function, suggesting a large role for reversible cell signaling and cell state in neurodegeneration.
Amyloid-β remains an important target in the development of Alzheimer's therapies. The failure of immunotherapies targeting amyloid-β are not stopping the expansion of efforts to test immunotherapies targeting both amyloid-β and tau - tau being more harmful than amyloid-β. Not all amyloid plaques are the same; those containing nucleic acids may be worse and more inflammatory, thus potentially explaining differences between individuals who appear to have similar levels of plaque. Enhancing a natural process by which cells ingest and break down misfolded extracellular proteins might be a basis for treating neurodegenerative conditions in which protein aggregates are important. TREM2 antibodies are explored as a way to encourage greater microglia activity to clear molecular waste and treat Alzheimer's disease. Other groups are looking into sequestration of amyloid-β into nanoparticles.
While Leucadia Therapeutics and EnClear Therapies continue to progress towards their respective approaches to dealing with the clearance of molecular waste from cerebrospinal fluid, more evidence continues to arrive in support of the role of reduced cerebrospinal fluid drainage (and thus reduced removal of waste products from the brain) in the development of neurodegenerative conditions. It isn't just cerebrospinal fluid; blood drainage from the brain also slows with age, with consequences to brain structure.
Biomarkers of Aging
The assessment of biological age is a growing concern. It is widely recognized that some way of reliably testing biological age is necessary to speed development of therapies capable of rejuvenation, to separate the wheat from the chaff, and direct resources to the best outcomes. Setting aside a few initiatives to construct biomarkers of aging from simple assessments of frailty, much of the present focus is on clocks derived from epigenomic, transcriptomic, metabolomic, and proteomic data gathered from populations at different ages. There are even clocks based on protein glycosylation, antibody binding, and ionomic (elemental composition of tissue) patterns.
These clocks are proliferating and specializing but it remains the case that there is no connection between the clock and the underlying damage processes that it reflects. Thus there is no assurance that any given clock will in fact accurately measure the outcome of a therapy: each would have to be calibrated for each type of intervention, using life span studies. There is every reason to expect these clocks to only partially represent the full portfolio of age-related mechanisms, or exhibit odd quirks, such as an underestimation of age in later life, or heart tissue showing up younger than other tissues. Nonethless, clocks are starting to be used in clinical trials.
Meanwhile, the research continues. Pulmonary aging correlates with epigenetic age acceleration. A clock was developed for skeletal muscle tissue, two more using metabolomics and the plasma proteome, then the RNAAgeCalc transcriptional clock, and yet another new transcriptomic clock. Many of the clocks have been compared head to head in large study populations, and the GrimAge clock is coming out ahead in such comparisons. Recently a the more accurage DeepMAge clock was developed using machine learning approaches.
Mitochondrial DNA copy number correlates with epigenetic age. Exceptionally long-lived individuals exhibit slower epigenetic aging. Blood metabolites can be used as a marker of frailty. Work on protein biomarkers overlaps with work on senescent cells, as the SASP contains many molecules that might be used to mark the progression of aging, as represented by an increased burden of senescent cells. The rate of germline mutations and certain molecular changes in the lens of the eye may also protentially provide a way to assess the pace of aging. Circular RNAs may be a useful basis for a biomarker of aging.
Follistatin gene therapy is still under investigation in animal models, and still shown to double muscle mass in mice. A more recent approach is DOK7 gene therapy, which regrows neuromuscular junctions to improve aged muscle function. Inhibition of mTORC1 also slows muscle aging via preservation of neuromuscular junctions. Further, CCR2 inhibition reduces inflammatory signaling to promote muscle regeneration in old mice, while upregulation of unacetylated ghrelin and 15-PGDH inhibition slows loss of muscle with age. Resistance training reliably improves muscle mass and strength in old people, and there are many ways to optimize this approach by combining training with various other interventions. Aerobic exercise boosts muscle stem cell activity. Molecular signals released by damaged muscle fibers promote muscle stem cell activity, for example.
Telomeres and Telomerase
Telomerase gene therapy is under development by a number of groups. It is considered a potential treatment for heart disease, among other age-related conditions. It may treat fibrosis via reducing the burden of senescent cells in old tissues. Other approaches to lengthening telomeres are under investigation, such as the use of small molecules to disrupt the balance of mechanisms in favor of more telomere lengthening activity in stem ells.
Cancer research is a vast field, and there is always far too much to note. Mortality rates continue to fall. The most important areas of cancer research are those that are likely to give rise to treatments that can impact many or near all cancers with little to no per-cancer adjustment required. They must target universal mechanisms that cancers cannot evade. There are simply too many cancer types, and too much evolution within any given cancer, to make meaningful progress otherwise. This year, researchers have suggested targeting lipid metabolism to suppress metastasis, MR1 as a signature of cancerous cells, use of the small molecule NU-1 to inhibit telomerase activity, lipid nanoparticles carrying calicum phosphate and citrate, inhibition of mitochondrial DNA transcription, and TREM2 antibody therapy.
In other parts of the cancer field, chimeric antigen receptor immunotherapies are expanding to use in macrophages as well as T cells. The immune response to cancer changes with age in ways that are far from fully understood, making the development of immunotherapies a more complex proposition than would otherwise be the case. Researchers have shown that cancer treatment increases cancer risk for cancer survivors. This may be mediated by the creation of excess senescent cells.
Stress Response Mechanisms
In this age of comfort, low-cost calories, and machineries of transport, all too few people are as fit as they might be. Yet fitness and activity is one of the most reliable interventions to reduce age-related disease and mortality, in this world still lacking widespread and proven anti-aging therapies. Even light physical activity is significantly better than a sedentary lifestyle when it comes to mortality risk. Being sedentary raises the risk of cancer mortality. A healthier lifestyle at age 50 increases healthspan by nearly a decade. The data keeps on arriving to reinforce this point, year after year. Training for a marathon reverses some age-related vascular stiffness and hypertension. Exercise improves memory via increased blood flow, and also correlates with improved functional connectively in the brain. Exercise acts through Wnt signaling to slow brain aging and also helps T cells kill cancer cells. Physical activity is a treatment for frailty, can actually reverse frailty to some degree, and produces beneficial metabolic adaptations mediated by myokine signaling, such as increasing ubiquitination to clear damaged proteins from cells. Physical fitness correlates with a lesser decline in gray matter with age.
Calorie restriction is, of course, the other long-standing and well proven existing intervention that can reduce age-related disease and mortality. A great deal of thought has gone into why the calorie restriction response evolved early in the history of life. Data arrives every year to reinforce the small mountain of evidence that already exists in support of the health benefits. Calorie restriction reduces the harmful chronic inflammation of aging, perhaps largely by suppressing the inflammatory SASP of senescent cells. Intermittent fasting is also shown to be beneficial in human patients, improving biomarkers in metabolic syndrome, and improving chemotherapy effectiveness while reducing side effects. In mice, it increases neurogenesis and accelerates wound healing. Calorie restriction slows muscle aging in non-human primates, and reverses gene expression changes in old rats, even when started late. Calorie restriction also slows the aging of microglia in the brain and improves intestinal stem cell and intestinal barrier function.
Most, and I would say too much, of present research and development related to the treatment of aging is focused on upregulation of stress response mechanisms, in attempts to mimic the benefits of calorie restriction and exercise. This cannot have a large enough beneficial outcome to be worth the effort. It won't add decades to healthy life spans. Nonetheless, it is the largest portion of the field today. Upregulation of autophagy is arguably the most important of these stress responses. Indeed, if autophagy is inhibited, then accelerated aging result, such as increased T cell inflammatory activity. Impairment of autophagy occurs with aging, for reasons that include the presence of protein aggregates, and is implicated in loss of stem cell function. It contributes to osteoporosis.
Strategies noted in this past year to upregulate stress response mechanisms engaged by calorie restriction or exercise include sestrin upregulation, use of the small molecule nilotinib, cyclin D1 upregulation, injection of metformin rather than oral administration, mTORC2 activation, TAT peptide delivery, increased levels of β-hydroxybutyrate, intermittent treatment with rapamycin, which some feel should be widely prescribed, HNF4α inbition, use of metolazone, and overexpression of Gpld1. Other approaches that boost stress responses include PASK deficiency, cAMP upregulation, lowered body temperature, and induction of mitochondrial uncoupling, given a safe way to achieve that goal. It is also possible to create many of the effects of calorie restriction by restricting intake of only one essential amino acid, such as threonine. Aspirin, of course, is also a calorie restriction mimetic drug that improves health via autophagy.
There is a small but energetic community of self-experimenters, interesting in assessing the outcomes of various strategies. I published a few notes on this topic over the past year. Firstly, an analysis as to why sex steroid ablation isn't a viable approach to thymus regeneration, at least not without a great deal more work on the part of the research community. Secondly, an outline for recreating a flagellin immunization study that was carried out in mice and noted to favorably adjust the gut microbiome. Other groups are trying to raise the bar on information for self-experimenters. Forever Healthy Foundation published a conservative risk-benefit analysis for the use of the dasatinib and quercetin senolytic combination.
Slowing Aging in Animal Models
Brd2 inhibition, astaxanthin based drugs, CDC42 inhibition via CASIN, low dose PPARγ agonist treatment, and overexpression of humanin have been found to slow aging in laboratory species for reasons that are either unclear, or involve many distinct mechanisms with little evidence for which are more or less important. In a case that is a little more cut and dried, mifepristone reduces innate immune driven inflammation in flies, slowing aging as a result.
Odds and Ends
There are always areas of research, some quite ambitious, some of it not, but nonetheless interesting, that don't quite fit into any of the usual buckets. This is a barnstorming era in biotechnology, in which it is possible to try all sorts of adventurous options to see if they can work, at least in principle. A selection follows. Increased expression of DICER has been suggested as a treatment for age-related macular degeneration as well as a way to improve the metabolic benefits of exercise in later life. Aging can be divided into "ageotype" categories based on how the common mechanisms develop into distinct patterns in different individuals. ELOVL2 upregulation reverses vision decline in aging eyes. Researchers have speculated that a downward trend in body temperature over the past few centuries reflects a lower burden of infection-driven inflammation, and thus is a feature linked to increased life expectancy.
Amyloid-β aggregation may be more than just a mechanism of Alzheimer's disease, but also a contributing cause of cardiovascular disease. Klotho is an area of interest because of its effects on aspects of aging. Recently delivery of soluable α-klotho was shown to reduce cardiac fibrosis in mice. The effects of klotho on life span may take place in part due to increased resistance to hypertension. Plasma transfer is an area of interest, in that transfer from young rats to old rats reduces measures of aging and senescent cell burden. A lower socioeconomic status correlates with faster age-related decline. Researchers have devised a way to provide photoreceptors with near-infrared sensitivity, as a way to restore light sensitivity in degenerating retina that have lost their normal visible light sensitivity, but retain cells able to function.
There is an age-related increase in CD47 expression that impairs vascular function, and inhibiting CD47 reverses this effect. Hyperbaric oxygen treatment may have some benefits, such as improved cerebral blood flow, but it doesn't seem likely that it truly reverses aging, such as via strong senolytic effects. Transcranial magnetic strimulation might be getting to the point of showing some reliable benefits to cognitive function in old people; the precise details of the technique used may be important, and thus few approaches will actually work. Thermoregulation is impaired by aging for reasons yet to be comprehensively explored. Despite failures of past years, some researchers continue to be interested in the use of laser light to break down harmful protein aggregates. Something like 30% to 40% of dementia might be avoided through better lifestyle choices. Increased insulin receptor expression improves memory in old rats. The story of C60 in olive oil came to a sad but predictable end. It is not in fact a viable was to slow aging, and the original study that suggested it was should be discarded.
Achieving healthy human longevity, a life that is vigorous and youthful in old age, is the challenge of our era. Work on the treatment of aging is expanding, but even though the old are becoming functionally younger, these are early years yet. Aging remains the largest and brightest unexplored new therapeutic frontier. Aging research should be a higher priority and enjoy far more funding given the prospects to improve the human condition - we should be trying to treat aging, and thereby improve many diseases, not continue treating the symptoms of aging on a disease by disease basis. Further, the future should involve a great deal more experimentation with combinations of therapies for aging. This is an underexplored area. Despite the promise of the field, a great deal of education and advocacy remains necessary: the public, and indeed many investors, cannot yet distinguish between scientific, unscientific, likely good and likely bad approaches to longevity. Those of us with a better idea of the nature of the field have a responsibility to spread our knowledge.