FightAging!
1-6-18

One should of course look at annual reports from the SENS Research Foundation and Methuselah Foundation issued earlier in the year before reading the following rambling collection of items that caught my interest. The most important research is that relating to the SENS goals of rejuvenation through repair of cell and tissue damage, but far more than that is taking place in the research community, even through it will largely prove to be less beneficial to patients.

Senolytics and Senescent Cells

Cellular senescence is now undisputed as a cause of aging, and efforts to destroy or control senescent cells are growing rapidly in scope. The first human trials of senolytic therapies to destroy senescent cells have started, and a mouse lifespan study demonstrated 36% extension of remaining life after late life administration in old mice. More life span studies are running, such as the one sponsored by Oisin Biotechnologies. New age-related conditions are linked to the presence of senescent cells seemingly every month, with results over the past year published for vascular dysfunction, Parkinson's disease (and all of the other synucleinopathies), sarcopenia and frailty, osteoporosis, impaired heart regeneration, cardiovascular and metabolic disease, idiopathic pulmonary fibrosis, the degeneration of bile ducts, retinal degeneration, loss of regenerative capacity in the liver, tau aggregation in Alzheimer's disease, autoimmunity, age spots, chronic obstructive pulmonary disease, and loss of hematopoietic stem cell function.

There is suddenly a wealth of funding for basic research into the cell biology of senescence and its mechanisms. A lot of review papers on the subject are being written as well; there is certainly no shortage of work to be accomplished. Earlier this year, evidence was provided for accumulation of senescent cells to be a function of immune system decline, and for lamin A mutation to contribute to normal aging via cellular senescence. Researchers are questioning whether or not senescent cell presence is dynamic in old tissues and the degree to which senescent cells accumulate because of immune system failure in aging. Existing cells are being discovered to be senescent: a well known problem population of monocytes turned out to be senescent, for example. It was also found that senescent cells accelerate the creation of more senescent cells. Researchers in the cancer community are pondering how to better use senescent cells to suppress cancer, given a clear way to remove them afterwards before they cause too much harm. Discovery of new markers and new mechanisms to enable selective destruction of senescent cells is becoming a well-funded, popular line of work. TIGIT, for example, has now been associated with senescent T cells. As another example, TXNIP is implicated in cellular senescence in mice and flies.

New data on senolytic therapies capable of destroying senescent cells is rolling in on a regular basis. Quercetin is not senolytic on its own, rather than in combination with dasatinib. There are plenty of other marginal senolytics in the pipeline, and candidates for which we only have cell data, such as the antibotics azithromycin and roxithromycin. New candidate senolytics with worthwhile effects in animal studies include tetramethylpyrazine, piperlongumine, and, strangely given the failure of quercetin, fisetin. Other approaches to destruction of senescent cells are also moving forward at varying speeds, such as immunotherapies and methods of targeting p16 expression. A research group has also demonstrated the basis for a general drug delivery system that preferentially targets senescent cells, which seems a promising development. Interestingly, calorie restriction suppresses senescent cell levels, though obviously by nowhere near enough.

Assays for level of senescence in humans remain a challenge, though there are some signs of movement; an approach based on blood samples and cell size was demonstrated earlier this year, for example, or the use of CD36 as a cell surface marker. The founders of the CellAge startup are still somewhere in development of their synthetic promoter approach. We shall see where it all leads. The senolytic companies still have little incentive to improve on tissue staining methods that work acceptably well in the lab but are unsuitable for human assays.

Some researchers are more interested in modulating senescence than in destroying these cells, which I can't say I think is a wise course of action at this point in time; it isn't cost effective in comparison to destroying these cells, and no-one has yet produced a compelling reason not to destroy them. MDM2 agonists are suggested as one approach to attenuate some of the harmful signaling produced by senescent cells.

Macrophage Polarization

The polarization of macrophages and microglia continues to be a topic of considerable interest in the research community, though it is anyone's guess as when this will make the leap to earnest efforts towards clinical translation. Some researchers have examined possible mechanisms to explain the age-related shift to harmful polarizations, but most are more interested in overriding the polarization state so as to covert harmful inflammatory immune cells into helpful regenerative immune cells. This may be useful as a therapy for heart failure, particularly ventricular hypertrophy, regeneration in the brain, prevention of cancer, or to enhance immunotherapy. Interestingly, oxidized lipids, one of the forms of metabolic waste identified in the SENS rejuvenation research proposals, may steer macropages into their harmful inflammatory polarization. Faltering autophagy may also be involved. Research this year has also shown that polarizations are more favorable in healthier old people.

Breaking Down Metabolic Waste

Clearing metabolic waste products inside and and outside cells is an important arm of the SENS vision for rejuvenation. Researchers this year linked accumulated waste in the lysosome to loss of function in neural stem cells, and in the progression of neurodegeneration in general. Upregulation of lysosomal activity enhances neural stem cell function. A team independent of the SENS Research Foundation made some progress towards finding bacterial enzymes capable of breaking down 7-ketocholesterol. Another group showed USP13 inhibition to clear Lewy bodies in neurons. Antibodies targeting oxidized cholesterols slowed the development of atherosclerosis in mice - as might be expected from the growing evidence for these damaged cholesterols to be a primary cause of atherosclerosis. Various groups are working on approaches to clearing transthyretin amyloid, linked to cardiovascular disease in the population at large, and to mortality in supercentenarians, some more promising than others.

Can the existing technologies of blood filtration be expanded to help with aging? There are all sorts of forms of molecular waste that might be cleaned out on a repeated basis. The costs would have to fall dramatically to make this sort of thing cost-effective, however. What about filtering cerebrospinal fluid (CSF) as well as blood? Even in early aging, CSF has waste in it that we'd be better off without. Evidence accumulates for failing drainage of CSF to be the start of neurodegeneration with age.

Regeneration of the Immune System

Regeneration of the aged immune system is a topic of great interest. New modelling published this year suggest that cancer risk is entirely determined by declines in T cell production. A novel approach to regrowth of the atrophied thymus, where T cells mature, was demonstrated this year, joining a range of others at various stages of development. The company LyGenesis, while initially focused on liver organoids, is working on placing thymus organoids into lymph nodes. Researchers also suggested this year that aged lymph nodes will need to be regenerated in order to restore immune function. Other groups are focused on restoration of hematopoietic stem cell populations, those responsible for generating immune cells, and which decline with age.

There is compelling evidence for cytomegalovirus (CMV) infection to be an important contributing cause of immunosenescence. Too much of the immune system becomes uselessly specialized to CMV, and too little is left to fight novel threats. New evidence in support of this hypothesis turns up every year, and this year was no exception. A study suggests the infectious dose correlates with immune dysfunction, while another group finds a specific immune population that results from CMV infection and contributes to cardiovascular disease. There are always, of course, opposing views, in which CMV is painted as a positive influence, but that is very much a minority viewpoint.

Mitochondrial Damage and Dysfunction

Damage to mitochondrial DNA is an important issue in aging, even though the way in which a single mutation in a single mitochondrial genome can cascades into overtaking all of the genomes cell is poorly understood. The latest mouse models of accelerated mitochondrial mutation are not behaving as expected, but on the other hand it is possible to link mitochondrial mutational damage and loss of stem cell function. More people are giving thought as to how to fix this problem. Sadly the options are still fairly limited, even given this year's proposals for targeted destruction of mutant mitochondrial DNA and use of AOX from non-mammalian species to bypass damaged electron transport chain complexes. The best of the options, the SENS proposal of allotopic expression, is still woefully underfunded in comparison to its potential. Nonetheless, the SENS Research Foundation team is at the point of undertaking mouse studies for their work. That allotopic expression is proven technically is beyond doubt, given that Gensight is at the phase III stage of trials with their focus on a single mitochondrial gene and inherited blindness conditions. Yet the funding for the other twelve genes is still hard to come by.

Beyond this issue of DNA damage, occurring in a small but significant population of cells, mitochondria also become more globally dysfunctional with age, leading to higher levels of oxidative stress, and an energy crisis in muscles and brain. New evidence also shows that mitochondrial dysfunction causes telomere shortening, chronic inflammation, and problems in T cells. There is far less of consensus on why this mitochondrial dysfunction occurs or how to tackle the problem. Specific details are still being uncovered, such as loss of ADP sensitivity, or a role for the mitochondrial transition pore.

Nuclear DNA Damage

Does stochastic nuclear DNA damage cause significant issues in aging beyond cancer risk? Simply counting mutation levels in any given cell population doesn't help, and it is impossible to say whether variations in DNA repair contribute meaningfully to natural variations in human longevity. The mainstream consensus is that nuclear DNA damage does significantly disrupt metabolism and tissue function, with some form of clonal expansion necessary to spread a harmful mutation into enough cells to produce these effects. Another argument is that stochastic nuclear DNA damage raises rates of cellular senescence - and we know that it requires only a small number of senescent cells to induce the dysfunctions of aging via their potent inflammatory signaling. An even more unified variant of this argument suggests mitochondrial dysfunction causes the nuclear DNA damage that then produces senescence.

The Quest for a Biomarker of Aging

Is it possible to build a biomarker of biological age that is robust enough to be useful and actionable? Efforts continue, with the epigenetic clock still front and center, and being improved step by step, but researchers are investigating other approaches, such as several attempts at the use of protein levels rather than DNA methylation. There is also a contingent who wish to combine very simple assessments with algorithms to produce a score that correlates better than any single assessment. Any number of new individual biomarkers were noted this year, such as MCP-1 and new oxidative markers. Alone these are not all that accurate, but might be combined into one of the algorithmic efforts.

Telomerase Gene Therapies

Interest in telomerase as the basis for therapy continues apace. Building on work in mice from past years, telomerase gene therapy has been demonstrated to reverse fibrosis, for example. More evidence accumulated this year for increased telomerase not to increase cancer risk in mice, as was originally expected of this sort of approach to pushing damaged cells back to work. Researchers have even proposed a means to enhance the activity of native telomerase to achieve similar effects without delivering more. BioViva Sciences appears to have moved away from building a telomerase gene therapy, but we do now have more of the story of that attempt and more data from the test subject this year. Libella Therapeutics are working now on a gene therapy for human use, and gave a brief overview at RAADfest earlier this year.

The Comparative Biology of Aging

In the comparative biology of aging, researchers attempt to learn from other species, with an eye to eventually perhaps building therapies to port over more favorable biochemistry into humans. Studies of long-lived naked mole-rats are an important part of this field. This species maintains its genome exceptionally well in comparison to other, shorter-lived rodents. The cancer resistance of naked mole-rats was further explored this year, with new mechanisms added to those already known. Naked mole rats apparently suffer cellular senescence, but seem unaffected by it, analogous to the way in which they exhibit high levels of oxidative stress without apparent harm. Beyond naked mole-rats and aging, researchers have reported on investigations of highly regenerative species such as the axolotl, searching for the secrets of organ regrowth, and on the exceptional cancer suppression of elephants.

Well Developed Ways to Modestly Slow Aging

A few approaches to slow rather than reverse aging have picked up steam in the past year. Firstly, there is now a set of mTOR inhibitors in clinical development, most targeted specifically to inhibition of mTORC1 rather than mTOR in general, and a bunch of others waiting in the wings for their turn. Recent research results show mTOR is involved in vascular aging. A clinical trial has shown that mTORC1 inhibition can improve immune function in late life.

Secondly, raising levels of NAD+ in order to improve mitochondrial function is also at the point of showing benefits in clinical trials in the case of nicotinamide riboside. Plain nicotinamide, on the other hand, doesn't do well in mice, suggesting considerable variations in effectiveness in the various methods of NAD+ upregulation on the market. New evidence this year shows that loss of NAD+ is linked to cellular senescence in some tissues, and that increased NAD+ helps hematopoietic stem cell function.

Thirdly, we might consider mitochondrially targeted antioxidants, also intended to improve mitochondrial function, of which several different types are either in development or already approved for treatment of some conditions. This year, researchers provided data for SS-31 to improve cognitive function in mice, while MitoQ improved vascular system function in a human clinical trial. There is also published data for the effects of MitoQ on a variety of biomarkers associated with aging.

Self-Experimentation

That mTOR inhibitors, NAD+ enhancers, mitochondrially targeted antioxidants, and most initial senolytic compounds are cheap and easily available has energized the self-experimentation community. They tend not to be robust in their reporting and care taken in assessing compounds, however. In an attempt to raise the bar a little, I posted a number of guides over 2018. They include chemotherapeutic senolytics, the FOXO4-DRI peptide, mitochondrially targeted antioxidants, and a simple starting example with MitoQ and niagen.

Alzheimer's Research

Alzheimer's research is so massively funded that it generates an outsized amount of news and research results. Ask most scientists who toil within the field, and they are suspicious that much of this effort is wasted. There is open rebellion against the amyloid hypothesis and the recent history of relentless failure of clinical trials of immunotherapies. Researchers are looking at other approaches, such as cell therapies, targeting herpesviruses or infection in general as a cause of amyloid aggregation, destroying or replacing microglia, targeting all protein aggregates in the aging brain and not just one, focusing on tau (this is a popular one), use of anti-amyloid small molecules, slowing progression of Alzheimer's via NSAIDS, or addressing changes in drainage of cerebrospinal fluid, including via the glymphatic system. Ironically, this is occurring right at the time at which the original course of immunotherapies to clear amyloid from the brain is finally starting to work, and in a couple of different ways. Was this all a waste, or the price of progress? There you will find disagreement and debate. Other interesting research from the year includes signs that Alzheimer's is reversible until major cell death occurs.

Stem Cell Therapies and Tissue Engineering

First generation stem cell therapies achieve their results via cell signaling, as the transplanted cells do not survive long. But which signals? Most signaling between cells is carried by means of vesicles, membrane-bound packages of molecules. The class of vesicle known as exosomes is gaining more attention these days, as researchers have found they are fairly easy to harvest. Why deliver cells when you can deliver vesicles? The first tests have been intriguing: vesicles of young cells can reverse measures of aging in old stem cells in cell culture, and similarly in old mice. Vesicles promote heart regeneration in rats, brain regeneration and intestinal regeneration in pigs. Exosomes from stem cells make skin cells more resilient.

Tissue engineering and regenerative medicine is too large and energetic a field by far to do more than note a few of the high points as they race by. This year a human trial showed that mesenchymal stem cell transplant reduced frailty in older patients. Some very promising progress is being made on ensuring survival of transplanted cells in the heart and in the retina, actually realizing the original goal of delivering useful, functional cells to support aged tissues. Researchers are also demonstrating the ability to grow patient matched tissue sections via induced pluripotency. The production of small functional sections of tissue, organoids, is progressing apace, as is bioprinting. Bioprinting efforts are in fact consuming large-scale venture funding in the production of factory operations now. Examples of tissues created by the research community include corneas, liver sections, salivary glands, and intervertebral discs. The development of decellularized organs for transplantation is also moving more rapidly. Researchers recently demonstrated transplantion of decellularized lungs in pigs. This year also saw the beginning of a contentious debate over whether adult neurogenesis happens in humans as it does in mice; the implications are important for near term progress in regenerative therapies for the brain.

Cancer Research

The cancer research industry is another vast field in which it is impossible to do more than sample the output of the scientific community. The important part of cancer research, to my eyes, is progress towards technologies that can be applied - with little alteration - to most or all cancers. This is the path to meaningful progress, given the vast array of cancers that exist. This year researchers noted that it may be possible to starve any cancer cell given the way they alter circadian rhythm mechanisms. Paligenosis has been noted as a process that might give rise to broadly applicable cancer therapeutics capable of suppressing cancer cell proliferation. Mechanisms of Huntington's disease might be used to suppress all cancers. Genes essential to metastasis have been identified as possible targets. There are suggestions of a potentially exploitable mechanism linking p53 and DHEAS. Meanwhile, CAR-T therapies, while not applicable to all cancers without a fair amount of work to adapt to each new type, are still proving to be a major advance over the prior state of the art.

Blood Pressure and Cholesterol

Blood pressure and cholesterol levels are important topics in the present practice of medicine. One of the great successes of medicine in recent decades, against all the odds, has been to find that blood pressure and cholesterol are so important to mortality that overriding bodily systems to bring them under control can significantly reduce mortality rates even given the fact that none of the underlying causes are being addressed, and even given ongoing debates over their importance. Research is progressing towards novel ways of achieving these goals, such as via ANGPTL3 blockade, PCSK9 inhibition, or any number of other gene therapies that reduce cholesterol levels or blood pressure. Researchers have also tried training the immune system to attack cholesterol transport mechanisms.

The Cryonics Community

Cryonics is ever controversial in the mainstream, but the press seems more respectful of late. The cryonics community advances and changes slowly, but nonetheless it does advance. Progress at a faster pace requires greater investment in research and development, which in turn is unlikely to arise absent commercial success in offering cryopreservation services. This chicken and egg is nothing new, and the bootstrapping process of incremental growth is a slow one - though with the occasional unexpected and welcome development, such as the donation of 5 million to Alcor this year to support cryonics research. That research is now moving more rapidly towards viable reversible cryopreservation of organs, something that would greatly improve the standing of the cryonics industry. Small molecule alternatives to cryoprotectant to minimize ice formation during cooling are under investigation, for example.

The long-standing tension between those who care only to see a copy of their mind running in the future versus those who want their living brain restored and repaired continues to be debated. This influences support for specific technical approaches, as noted by the Brain Preservation Prize going towards a vitrifixation method that is advantageous for copying the structure of the preserved brain, but makes restoration of the tissue far more challenging, one step removed from being impossible. The company Nectome was founded to commercialize this approach with the explicit aim of providing data for later whole brain emulation. From my perspective, it would be good to see the pendulum swing back to favor improvement in reversible vitrification preservation options.