Fight Aging!

At the end of 2022, we can reflect on the fact that we are steadily entering a new era of medicine, one in which mechanisms of aging are targeted rather than ignored. It is a profound change, one that will change the shape of a human life and ultimately the human condition by eliminating the greatest sources of suffering and death in the world. Year after year, we see increased funding, ongoing progress towards therapies capable of slowing aging or reversing aspects of aging, and a growing taxonomy of such potential therapies and their target mechanisms.

The view of aging in the medical community and public at large is changing, slowly, in the face of this, such as the recognition that the long-established practice of dividing aging into many different diseases and treating them one by one isn't working. To fight aging one must tackle the causes of aging, and each cause contributes to multiple conditions. One day in the not-so-distant future, the average person in the street will see aging the same way that he or she presently sees cancer, meaning that it is obviously a research priority, something that should be treated and cured.

The Longevity Industry and Associated Non-Profit Initiatives

The longevity industry continues to grow and diversify, and there are now far too many companies and too many venture funds for any one observer, and certainly not this one, to keep up with new teams, new funding, and new projects. Much the same could be said for the non-profit space. The organizer and volunteers at AgingBiotech.info are certainly doing their best to maintain a useful, up-to-date resource, however!

That said, I will note a few items, starting with one sizable fund, Kizoo Technology Ventures, that was profiled earlier this year. It is an important fund because its principals specifically focus on the SENS view of aging: the importance of molecular damage, and the point that rejuvenation will only be achieved by repairing that damage. The SENS Research Foundation released its annual reports a few months ago, and it is, as always, interesting reading for those interested in the science of rejuvenation. Aubrey de Grey has launched a new non-profit, the Longevity Escape Velocity Foundation that will focus on similar work to that conducted at the SENS Research Foundation, with an emphasis on repairing the cell and tissue damage that causes aging.

Fundraising activity was quite energetic prior to the recent market downturn. While many of these companies are actually working on drug discovery platforms or next generation dietary supplements or other low-hanging fruit rather than bold new therapies, there are nonetheless exciting biotechnologies under development as well, true means of rejuvenation. We'd always want to see a larger portion of the industry undertaking that sort of work, but it is what it is. As growth occurs, it is interesting to see the rush to moderation in messaging. It is a longevity industry, yes, but one in which the larger players are quick to reassure the world that they are not in fact trying to produce longevity.

Cellular Senescence

Cellular senescence is an important contributing cause of aging, in that the burden of senescent cells rises with age, and these cells disrupt tissue and organ function with their pro-growth, pro-inflammatory signaling. Researchers are optimistic regarding the potential of therapies targeting senescent cells, even the cautious types, and so is the popular science press. In just the last year, many studies have reported slowing or reversal of specific aspects of aging via clearance of senescent cells, or otherwise implicated senescent cells in disease progression. A partial list: neurogenesis; neuronal function; Alzheimer's disease, liver disease; kidney aging; T helper cell function; atrial fibrillation; reducing pain but not cartilage damage in osteoathritis; loss of microvasculature; atherosclerosis; fibrosis and inflammation in NASH; diabetic macular edema; particularly senescence in vascular smooth muscle; pulmonary fibrosis, amyotrophic lateral sclerosis; chronic obstructive pulmonary disease, and age-related loss of pulmonary function via a range of mechanisms; failure of organ transplants; loss of regenerative capacity in the heart; cardiovascular disease in general; cognitive function and brain aging in late life; amyloid aggregation in the vasculature; sarcopenia via reduced stem cell function; osteoporosis was frequently discussed; disc degeneration; vascular calcification; Parkinson's disease, such as via removing senescent microglia; improving ischemic stroke recovery; accelerated aging due to induction of cellular senescence by chemotherapy and radiotherapy; abdominal aortic aneurysm; immune function in the brain; gum disease.

Clearing senescent cells should be synergistic with stem cell therapies and partial reprogramming, both combinations expected to provoke regeneration. Senolytics should also be synergistic with cancer therapies, providing better patient outcomes with fewer long-term side-effects. These combinations should receive more attention! Further, some research suggests that combinations of senolytics may synergize to improve on the results of any single drug.

New clinical trials continue to be launched for established senolytics, including one for Alzheimer's disease, and senolytics as a class are approaching clinical use. Novel approaches to reducing the burden of senescent cells continue to emerge as the wheels of drug development begin to turn in earnest. Those mentioned in the last year include the following: use of 25-hydroxycholesterol; improving the efficiency of natural killer cells via several approaches; mitochondrial transfer; applying partial reprogramming to senescent cells, something that continues to seem a bad idea; MCL-1 inhibition; control of viral infection; YAP upregulation; mitochondrially targeted tamoxifen; glutaminase inhibition; overexpression of GPNMB; inhibiting the BDNF-TrkB interaction; p53 upregulation; SFRP4 inhibition; overexpression of DDIT4 and HDAC4; PD-L1 checkpoint inhibition; GATA4 inhibition; USP16 inhibition; reducing mitochondrial dysfunction to prevent the onset of some cellular senescence; targeting antoxidants to telomeres; nintedanib, a similar drug to dasatinib; derivatives of FOXO4-DRI.

Mitochondrial Dysfunction

Mitochondrial dysfunction is a prominent feature of aging, and is accompanied by a decline in mitophagy, meaning the cell maintenance processes of autophagy targeted to mitochondria. Attempting to upregulate mitophagy is a popular topic, with approaches mentioned this year including urolithin A (and a clinical trial), BNIP3 upregulation, and iterations on spermadine. Unfortunately none of the easier, supplement based approaches appear to be any better than exercise or calorie restriction when it comes to improve the operation of autophagy in older individuals. There are other stress responses that can be triggered to improve mitochondrial function, such as the unfolded protein response, influenced via protein import mechanisms.

A range of other potential paths to reversing mitochondrial dysfunction are under development. Reprogramming is one of the more prominent, followed by the various groups developing the basis for mitochondrial transfer therapies. Researchers recently demonstrated editing of mitochondrial DNA in vivo, though it seems challenging to use this technology to deal with stochastic mutational damage. The role of mitochondrial DNA mutation remains much debated, both for and against. Other approaches mentioned this year include: enhancing mitochondrial fission to restore the imbalance in mitochondrial dynamics; magnetic fields used to improve mitochondrial function; use of antifibrosis drugs to improve mitochondrial metabolism; use of mitochondrially derived peptides; sirtuin upregulation; upregulating NAD levels via NMN supplementation and CD38 inhibition; partially inhibiting complex I of the electron transport chain; and mitocondrial uncoupling via newer, safer means than in past decades. Too few of these approaches seem likely to have large effect sizes, unfortunately.

Clocks for Aging

The number of clocks that assess biological age, derived from omics data and other measures, is proliferating rapidly. Even only considering epigenetic clocks the number is steadily increasing. Fortunately, at least some effort is being put into comparing clocks in order to winnow out the less helpful ones. New clocks noted this year incuded: a retinal image clock; a metabolomics clock; a clock for naked mole-rats; and a lipid clock.

This broadening of work on clocks is taking place because a consensus measure of aging would revolutionize the field, enabling rapid, directed progress towards the best approaches to treat aging as as medical condition. This point is widely recognized. We are not there yet, however, as the clocks developed to date are not yet well enough understood. Despite a few inroads, the connections between epigenetic aging and the rest of aging are not yet well mapped.

There appear to be some odd blind spots in many clocks, such as inflammatory status and biases in centenarian epigenetic age. Reduced epigenetic age does not prove slowed or reversed aging, we should probably be suspicious of clocks that use few data points, and all studies measuing clock data must also measure other metrics of health and disease. This state of affairs is not preventing speculation as to whether the existence of cross-species clocks should mean that therapies that actually address root causes of aging should perform equally well between species, or that epigenetic clocks will point the way to a true identification of the causes of aging.

Partial Reprogramming

There is so much money flowing into the exploration of partial reprogramming with Yamanaka factors and potential alternatives, in order to restore more youthful epigenetic patterns and thus more youthful cell behavior, that we're going to see a great deal of coverage, even in the popular press, in the years ahead. Hopefully the obstacles are overcome, such as the inclination of natural killer cells to attack reprogrammed cells, and the techniques improved, and this turns out to be a viable path to rejuvenation at the end of the day. It can't fix everything, but we can hope that it will positively influence many aspects of aging.

The fundamental research in animal models is getting funded as well, and continues apace. Progress in understanding and capabilities is quite rapid. If interested in the present state of play and the road to the clinic, there were a number of popular science overviews published following the large-scale funding of Altos Labs and other companies. Alternative approaches to reprogramming beyond Yamanaka factors are being considered. Is it possible to reprogram effectively with small molecules? Time will tell. Researchers are starting to think about the specific conditions they might treat with reprogramming approaches. Some of those metioned in the last year include: disc degeneration; T cell exhaustion resulting from cancer; and liver injury.

Neurodegeneration

Neurodegeneration is connected to near all of the mechanisms and environmental factors studied in the context of aging. Novel approaches to the treatment of neurodegenerative conditions are constantly suggested, and existing approaches mentioned while under development. A selection from the past year includes the following items: the use of disaggregases to clear amyloid, while noting that amyloid is still the primary focus in Alzheimer's treatment, despite continued failures in clinical trials; forcing microglia into the anti-inflammatory M2 polarization, or clearing them entirely; TREM2 antibodies to prevent the incapacity of microglia in the aging brain; transfer of cerebrospinal fluid from younger donors; a combination of rapamycin, acarbose, and phenylbutyrate; adjusting the aging gut microbiome; greater control of viral infection, particular those involving herpesviruses capable of persistent infection; whole blood exchange to encourage amyloid-β to leave the brain into the vasculature; reprogramming astrocytes into neurons in vivo; drugs to decrease microglial inflammation slow neurodegeneration in early stages; influenza vaccination correlates with a 40% reduced Alzheimer's risk; transcranial direct current stimulation; provoking greater activity in neural progenitor cell populations; Atoh1 gene therapy to regenerate hair cells in the inner ear; activating or somehow expanding the limited supply of precursor neurons; immunization against amyloid-β; use of plasmalogens; GM-CSF treatment improves memory in mice; enhancing neurogenesis to treat Alzheimer's, such as via upregulation of oxytocin.

The good news is that manifestations of neurodegenerative processes, such as cognitive impairment, are in decline, and those on the path to dementia can now be screened early, years in advance of symptoms. This lowered risk is likely the result of improved cardiovascular health, while individually reduced risk is offset by the aging and growth of the population, leading to higher absolute incidence of disease. Being fitter correlates with better late life cognitive function, and exercise with improved synaptic function, as well as improved brain function more generally. Physical fitness also clearly reduces dementia risk and improves brain function, perhaps largely via lowered blood pressure, with as much as 40% of dementia cases being the result of lifestyle choices.

Aging of the Immune System

Chronic unresolved inflammation is a key feature of aging. Immune system aging is these days described as a mix of immunosenescence and inflammaging; every year a few review articles discuss the definitions and relationship between them. Important areas of declining function include the thymus and hematopoietic populations in the bone marrow, though every aspect of the immune system shows loss of function. The thymus atrophies with age, a sizable contribution to the decline of the adaptive immune system. Modest calorie restriction in humans has been shown to produce a surprisingly large regrowth of active thymus tissue, a surprising result that suggests the thymus is more dynamic in adults than suspected. KGF overexpression and introduction of subpopulations of thymic cells produces an enlarged thymus in animal studies, but would need a clever delivery mechanism to get the therapy into the thymus in humans.

Various approaches are under consideration to reverse immune aging, either generally or focused only on narrow issues within the broader set of problems. Lowering the lifetime burden of infection will likely slow hematopoietic aging. Upregulation of autophagy might help slow immune aging. A gene therapy delivering a BPIFB4 variant improved immune function in old mice. PGD2 inhibition can help with the slowdown in some narrow aspects of immune cell communication, improving the immune response. Trained immunity is an interesting phenomonen in which some challenges can improve innate immune function in late life. For example, vaccination with mycobacterium vaccae suppresses chronic inflammation. Calorie restriction has similar effects on innate immune system activation. Lowering inflammation may be a useful treatment for frailty. Targeting the inflammasome may be an improvement on current very blunt methods of suppressing inflammatory signaling, and clearing senescent cells to remove their inflammatory signaling should also help greatly. Other approaches to lowering inflammation mentioned recently include resistance training in older adults and reduced SPARC levels in fat tissue.

The Gut Microbiome in Aging

The balance of populations in the gut microbiome changes with age in detrimental ways, such as via increasing inflammatory signaling, producing harmful metabolites, or a diminished production of beneficial metabolites. This impacts health, and numerous correlations can be drawn between the activity of the microbiome and various manifestations of aging. Adjusting the gut microbiome in lasting ways to restore youthful populations may or may not achieve that much more than choosing a good program of exercise and diet, but it can be accurately measured. One can determine exactly what happened following any given intervention via the sequencing of microbes from a stool sample. Various approaches move the needle, and those in the spotlight this past year include: calorie restriction and methionine restriction; fecal microbiota transplantation was shown to improve function in mice, and this approach was a particularly popular topic in the lead in to FDA approval of one implementation and a few results in aged humans; oral administration of Akkermansia muciniphila; and heterochronic parabiosis, the latter obviously more interesting than useful.

Cardiovascular Disease

Atherosclerosis and consequent cardiovascular disease is the largest single cause of human mortality, and should be a high priority in research and development. A great deal of evidence points to the inflammation of aging as a major driver of atherosclerosis. At the core of the condition, there is macrophage dysfunction where cholesterol overwhelms cells in artery walls. Calcification of vascular and heart tissue occurs in parallel with atherosclerosis, and is known to raise the risk of stroke as well as other cardiovascular events.

Numerous approaches have been suggested in the past year as treatments for cardiovascular diseases and their consequences: upregulation of autophagy; TRPM2 inhibition; targeting matrix vesicles to reduce pro-calcification signaling; CCL17 inhibition reduces inflammation in cardiac hypertrophy; an oligodendrocyte cell therapy, the cells responsible for generating myelin, improves stroke recovery, as does PTPσ inhibition; influenza vaccination can reduce inflammation to reduce stroke risk. Cholesterol continues to be the primary focus of therapeutic development in cardiovascular disease, such as via upregulation of reverse cholesterol transport. Atherosclerosis is in principle highly preventable, and early detection of atherosclerotic lesions might encourage greater success on this front.

Vascular stiffening is a major feature of aging. It is driven in part by degeneration of elastin, but has a broad range of contributing mechanisms. It contributes to many pathologies, even only considering the downstream effects of resulting hypertension, such as vascular restructuring and pressure damage to delicate tissues. Controlling hypertension greatly reduces risk of stroke. Targeting the inflammasome in vascular tissues or the use of SGLT2 inhibitors may reduce the aforementioned vascular dysfunction. Inhibition of piezo1 signaling may block the connection between hypertension and vascular hypertrophy.

Cancer

Cancer is the second largest cause of mortality in our species. It is a numbers game: damage and cell replication versus the odds of the wrong combination of mutations occurring in a cell, leading to unfettered replication. We might imagine that any narrow rejuvenation therapy that improves regeneration and increases cell activity in later life, such as improving mitochondrial function, for example, is going to increase cancer risk. Still, it is clear that a better lifestyle more than halves cancer risk, even just considering exercise.

We might argue that targeting theraputics to cancer cells is the true key to success in treating cancer. Prodrugs are one way to achieve that goal, ensuring that the drug is only active in cells with certain chemical characteristics. One of the reasons why immunotherapies are an improvement over the older approaches of chemotherapy and radiotherapy is that immune cells inherently provide the basis for a targeted approach. Early CAR-T therapies are looking good; long-term remission has occurred in a significant number of patients. Since then, many potential approaches to improve immunotherapies have emerged, such as via engineering T cells to reduce exhaustion in the face of exposure to cancer cells, replacement of checkpoint inhibition with new varieties of T cell therapies, or mRNA cancer vaccines.

Regenerative Medicine

Cell therapies and extracellular vesicle therapies of various sorts are under development for many conditions, including those in which cells are made universal to allow transplantation between individuals, though arguably we don't well understand the more widely used forms of stem cell therapy that presently exist. Some of the stem cell and vesicle therapies mentioned in the past year follow: cell therapies for degenerative disc disease and spinal cord injury; stem cell derived vesicles can reduce epigenetic age; cells sourced from the peripheral nervous system can be used to treat neurodegenerative conditions; brain regeneration might be achieved through suitable cell therapies; first generation stem cell and exosome therapies can upregulate neurogenesis; improving muscle regrowth with vesicles, and using exosomes to treat ventricular arrhythmia­.

Beyond cell therapies, growing and then implanting organoids may have utility, augumenting aged organs with new and functional tissue. Additionally, the use of scaffold material implants continues to be developed, such as for regrowth of dental pulp. Further, organ replacement may benefit from the advent of engineered pig organs; the first such heart transplant was performed this year, but the challenges encountered suggest that a longer road than hoped lies ahead before widespread use.

Is it possible to manipulate native cells to induce regeneration? Targeting fibroblasts to alter their behavior may enable scarless healing in mammals, for example, or reprogramming fibroblasts to cardiomyocytes in the heart. Engineering regrowth of organs in adults is potentially possible, given that highly regenerative species are capable of it, and non-regenerative species can perform much the same feats of regeneration during embryonic development. Enhancer sequences from zebrafish can be used to spur heart regeneration in mice. Further, researchers managed to imperfectly regrow frog limbs using a cocktail of growth factors; the result was not a fully formed limb, but that it worked at all suggests that this line of research may have potential.

Regulation of Medical Development

Early in the year, I noted a charitable view of the problems at the FDA regarding the development of drugs to treat aging. Meanwhile the wrangling continues over the question of whether largely unaccountable international bodies will decide to classify aging as a disease, something that is of importance to the regulation and funding of medicine and medical research, but irrelevant to the science itself. Longevity industry companies involved in developing therapies to treat aging are ignoring this circus in favor of picking specific diseases of aging and proceeding through the regulatory gauntlet as-is, in expectation that widespread off-label use will result. Still, comparatively few trials of genuinely age-targeted therapies have yet taken place. These are still early days.

Cryonics and Cryopreservation

That there should be more support for cryonics research and development is a popular viewpoint in that side of the longevity community. Until recently, cryonics was largely a non-profit industry. It has been proposed that a path to for-profit cryonics might involve first starting a hospital (or a veterinary clinic), and then adding cryonics services to that business, rather than starting with dedicated cryonics providers. Some new capabilities may pay off more than others when it comes to generating greater funding and growth for the cryonics industry, such as reversible vitrification of organs for use in transplantation. At some point in the future, a tipping point will be reached, and cryonics will have its time in the sun, just as the once-fringe field of rejuvenation research is enjoying that time in the sun today.

Rewarming tissue for use without damaging cells, structures, and function is arguably the real challenge in cryopreservation; in the last year use of magnetic nanoparticles has shown potential as a solution that might at least be applied to organs intended for transplantation.

Thoughts and Short Essays

I occasionally set down a few thoughts on topics relevant to longevity. Here are the few times that happened in the past year:

• Be Extraordinary or Be Dead
• Request for Startups in the Rejuvenation Biotechnology Space, 2022 Edition
• A Hypothetical Project: the Fast Track to Partial Reprogramming in Human Volunteers
• Should I Actually Be Working on Cryonics Rather than Rejuvenation?
• Understanding Anencephaly as the Start on the Road to Building Replacement, Youthful Bodies
• Is Reversing Paracrine Senescence a Useful Approach to Alleviating the Age-Related Burden of Senescent Cells?
• Distributed Full Disclosure Medical Development
• A Short Commentary on Why We Advocate for Aging
• Reporting on a Study of One with Khavinson Peptides and Melatonin for Thymic Regrowth
• Two Year Update on a Study of One with Flagellin Immunization to Adjust the Gut Microbiome
• Notes from the Rejuvenation Startup Summit, Held in Berlin in October 2022
• Year End Charitable Donations to Help Advance Rejuvenation Research

Onwards!

Things move slowly when you look at the world a year at at time. They run quite fast when comparing today with ten years ago, or ten years from now. There was no such thing as a longevity industry ten years ago, for example. Ten years from now, doctors will be widely prescribing the first rejuvenation therapies, and it will be the common wisdom that one can and should be treated to slow and reverse processes of aging. We live in interesting times, a great transition over decades from a world in which aging was thought of as immutable to a world in which aging is just another medical condition to be addressed.