Fight Aging! Newsletter, October 18th 2021

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  • Arguing for a Central Role of Cellular Senescence in the Age-Related Susceptibility to Inflammatory Conditions
  • The Early Years of Mitochondrial Transplantation as a Therapeutic Strategy
  • Gene Therapies Make Compensatory Metabolic Adjustment More Precise, But That Still Isn't Damage Repair
  • The Supplement Industry is a Corrosive Presence, Lacking in Integrity
  • Towards a Small Molecule Approach to Thymic Regeneration
  • Extra Thymi and Lesser Thymic Involution with Age in Long-Lived Naked Mole-Rats
  • Earlier Hypertension Correlates with Smaller Later Brain Volume and Raised Risk of Dementia
  • Exploring Mechanisms by Which Exercise Slows Cancer Progression
  • Greater Expression of Mitochondrial Base Excision Repair Enzymes in Longer-Lived Mammalian Species
  • Engineered B Cells as an Approach to Cancer Therapy
  • Lithium Produces Mildly Positive Effects on Healthspan in Mice
  • Senescent Cells Hinder Fracture Repair, Rather than Helping as Might Be Expected
  • The Rejuvenome Project Announces Collaboration with the Buck Institute
  • An Example of Senomorphic Drug Discovery
  • A Trial of the Senolytic Fisetin as a Treatment for Older SARS-CoV-2 Patients

Arguing for a Central Role of Cellular Senescence in the Age-Related Susceptibility to Inflammatory Conditions

Inflammation is a necessary part of the immune response to injury and infection, required in order to defend and rebuild. Normally, inflammation is a cycle of signaling that changes cell behaviors, response followed by resolution. When resolution fails, serious consequences can result. Conditions such as sepsis and severe COVID-19 cases are examples of a runaway inflammatory response leading to a high mortality. Both of these examples are age-related, in the sense that old people are far more susceptible to undergoing such a breakdown of the normal inflammatory feedback loops. The age-related dysfunction of the immune system predisposes it to overactivation and inflammation, just as it also makes the immune response less effective.

Senescent cells accumulate with age. These cells are constantly created and cleared in the body, and when present for only a short time play an important role in cancer suppression and wound healing. With age, however, the pace of creation accelerates and pace of clearance by the immune system slows. A constant presence of senescent cells allows their inflammatory, pro-growth senescence-associated secretory phenotype (SASP) to grow to pathological levels, encouraging a rising level of chronic inflammation throughout the body. It is hypothesized that this is an important cause of age-related susceptibility to runaway inflammation in response to circumstances that the regulatory mechanisms of young individual would successfully cope with.

Senescence-associated hyper-activation to inflammatory stimuli in vitro

Advancing age is associated with a multitude of physical and physiological deteriorations that leave the elderly susceptible to a wide variety of pathological conditions. Consequently, there is a steep decline in the health-related quality of life for the elderly. Amongst a wide variety of conditions, increased susceptibility to severe infections (such as COVID-19) and inflammatory conditions (such as sepsis) is one such age-related phenomenon. Despite representing under 25% of the population, people older than 60 account for more than 75% of sepsis related death. With respect to COVID-19, people over 60 are three times more likely to die from a severe infection than people under 60. The severity of disease progression in these population upon infection is partially attributed to the higher prevalence of severe cytokine storm in the elderly. Though there are many theories as to what makes the elderly susceptible to severe cytokine storm, there is no commonly accepted explanation to this phenomenon.

Cellular senescence is a phenomenon by virtue of which stressed or damaged cells undergo a permanent cell cycle arrest. In healthy individuals, senescent cells (SnCs) are cleared rapidly by the immune system. This clearance mechanism has been shown to become impaired with advancing age, leading to the accumulation of SnCs. In turn, the accumulation of SnCs has been implicated in many age-related pathologies and diseases. The detrimental effects of SnCs are partly a consequence of their expression of the senescence-associated secretory phenotype (SASP). The SASP includes an extensive list of factors such as inflammatory cytokines, chemokines, and matrix metalloproteases (MMPs), which are detrimental to the normal functioning of neighboring cells.

Hence, we hypothesized that SnCs contribute to the increased severity of infectious diseases and infection-mediated cytokine storm in the elderly through the expression of the SASP. To test this hypothesis, we examined whether SnCs exhibit hyper-activation to LPS, IL1β, and TNFα stimulation. Our results show that SnCs indeed have a greater proclivity to become hyper-activated in response to inflammatory insults, resulting in the increased production of a variety of inflammatory cytokines and chemokines when compared to their non-senescent counterparts, which we term senescence-associated hyper-activation. Senescence-associated hyper-activation may be attributable to a higher basal activation of the p38 mitogen activated protein kinase (p38) and NF-κB pathways. These findings lay a foundation to elucidate the important role of SnCs in the age-related increased susceptibility to severe infections and inflammatory conditions.

The Early Years of Mitochondrial Transplantation as a Therapeutic Strategy

Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP). Throughout the body, mitochondrial function declines with age, leading to corresponding declines in tissue and organ function. This universal malaise appears to be a downstream consequence of the underlying causes of aging. Those causes in some way lead to changes in gene expression that alter mitochondrial dynamics in ways that reduce the efficacy of the quality control mechanism of mitophagy. When not regularly destroyed, worn and dysfunctional mitochondria accumulate, and ATP production suffers.

It is possible to achieve benefits by introducing replacement mitochondria? Won't they just succumb to the same problem due to the aged environment? Eventually, yes, most likely. But studies to date suggest that the benefits of mitochondrial transplantation can large enough and long-lasting enough to be worth pursuing, even if the benefits fade over time.

Cells will readily take up whole mitochondria from their environment, and thus the immediate hurdles are largely a matter of logistics: being able to reliably generate and characterize mitochondria in the vast numbers needed to make a difference to cell function throughout the body. Once that is possible, then a range of further questions can be explored: duration, safety, long-term effects, whether transplanted mitochondrial DNA must match the recipient, or whether it can be improved upon, and so forth. A number of biotech companies, such as cellVie and Mitrix, are working to develop mitochondrial transplantation as a basis for therapies, so the next few years will be an interesting time in this part of the field.

Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy

It has been shown that mitochondria can be transferred both artificially and under normal physiological state. We can transfer mitochondria as a "cybrid" or treated isolated mitochondria directly into the cells or tissues. We can also transfer mitochondria by co-culture cells as a normal physiological state. Mitochondria transfer from one cell to another cell occurs especially when the mitochondria are injured. Therefore, the mitochondrial transplantation from healthy cells to abnormal cells is thought to be a novel and attractive therapeutic concept. It has been reported that mitochondria and/or organelles transfer between cells through tunneling nanotubes.

Replacement of damaged mitochondria with healthy mitochondria has been developed in order to overcome mitochondrial diseases and mitochondria dysfunctions. It has been shown that mitochondrial transplantation (mtTP) rescues ischemia reperfusion-induced damage and protects the brain from apoptosis. Current clinical and preclinical studies utilizing mtTP have been conducted or are in progress for the treatment of heart ischemia, brain ischemia, sepsis, cancer, acute kidney injury, and theoretically for any disorders in which mitochondria are damaged and disrupted.

We have demonstrated that mitochondria from a non-cancer cell line can be transplanted into cancer cell lines that lack mtDNA (ρ0 cells). This mitochondrial transplantation has been checked using MitoTracker, which can stain mitochondria, and confirmed that the healthy stained mitochondria from fibroblast cells have certainly transplanted into ρ0 cells. Recently, in a clinical trial, it has been shown that mtTP leads to cardio protection. It has been reported that mtTP ρ0 cells have decreased intracellular Fe2+ levels and downregulation of aquaporins. Since aquaporins regulate H2O2 permeability, these cells exhibit H2O2 resistance compared with the non-mtTP ρ0 cells. Thus, mtTP may enhance mitochondrial function that will allow for the rescue of cells and restoration of normal function.

Taken together, these results indicate that mtTP may be an upcoming effective therapeutic option. Therefore, mtTP is a very promising technique, which may be applicable for the treatment of many diseases including cancer. However, mtTP is only in the beginning stages of development, so further investigation will be needed to address various technical and ethical issues.

Gene Therapies Make Compensatory Metabolic Adjustment More Precise, But That Still Isn't Damage Repair

Given a suitable delivery system, one that localizes to the desired target tissues to a far greater degree than to all other undesirable off-target tissues, the big advantage of a gene therapy is it precisely achieves the manipulation desired. It dials up or dials down expression for selected genes, alters the amount of proteins produced from those genes, and thereby changes cell behavior as a consequence - and that is all it does. One doesn't have the endless concern about off-target effects that characterize small molecule drug development.

There are, of course, different challenges. Setting aside some adventurous technologies that won't be deployed in therapies any time soon, manipulating a few genes at a time is the present practical upper limit on gene therapy. Further, there is no viable delivery system for most target tissues in the body, if the goal is to maximize expression in a limited set of locations. Yes, a great many interesting technologies exist for use in animal studies, but the bounds of the possible are more limited when it comes to what is permitted in the clinic. Injecting a gene therapy vector into the bloodstream means that most of it will end up in the liver, lungs, and heart, and very little in lesser, smaller organs. Injecting a vector directly into tissue is prohibitively risky for most internal organs except in cases of very serious disease.

Another pressing issue is that there is no proven gene therapy vector that can produce months of expression. Too long an expression is as much of a problem as too short an expression when it comes to treating disease. The only options on the table are (a) permanent changes via integration into the genome, (b) non-integrating viral vectors such as AAV that produce expression that can last for years, (c) very short term expression changes via RNA therapies that might last a few days. In principle, plasmid delivery can produce expression that lasts for months, but no-one has yet robustly solved the very poor expression characteristics of plasmids once delivered into a cell. They just don't want to localize to the nucleus where they need to be in order to express.

Yet another problem: viral vectors are the most effective, but a given vector can be used once in a given individual. Thereafter the immune system will clear further doses before they can take effect. For some of the older vectors, a fraction of the population is already reactive to some variants, and must be screened out. In general, the immune system is the dose-limiting concern for most gene therapies. If it takes too much notice of a therapeutic, serious side-effects can result due to an inflammatory response. There are groups working towards ways to cloak vectors, but none are yet clinically approved, robust, and ready to be used for arbitrary therapies.

In summary, most of the challenges inherent in developing gene therapies revolve around delivery. The other hurdles are much less of a problem, and there are many groups working on solutions at various stages of development. What the industry is waiting for is a good delivery system that overcomes the issues noted above. That would enable a sudden blossoming of gene therapies.

A last point to made about gene therapies is that yes, they are the future of medicine when it comes to manipulating cellular pathways, in principle much more precise and capable than small molecules. Bigger effects are possible, with fewer side-effects. But if gene therapies are only used to adjust the operation of an aged metabolism, forcing a restoration of the expression of important regulatory and signaling genes to youthful levels, without addressing the underlying causes of those age-related changes in gene expression, then they are still only a compensatory therapy. The same limits apply here as for small molecule compensatory therapies: change one consequence of damage, and all the other consequences are still there. In a complex, interacting system, the benefits of such a strategy are necessarily limited.

Gene therapies and small molecule therapies can be rejuvenation therapies, repairing damage. They can be used to target deeper causes of aging. Senolytics, for example, are largely small molecule drugs that achieve the goal of selectively destroying senescent cells. The important thing is not the methodology but the goal, removal of a form of damage that is as close to the root causes of aging as possible, with many downstream consequences alleviated as a result. As today's short article notes, that is not what Rejuvenate Bio is doing. They are producing compensatory gene therapies, aiming at targets that allow a clear demonstration of superiority over small molecule strategies. But the upside remains limited by the underlying damage of aging, still there, still causing all of the other harms it is capable of.

Rejuvenate Bio is Reversing Age-Related Diseases to Increase Healthspan

"Today we think about aging as a dysregulation of genes and proteins that lead to age-related diseases, such as heart disease, obesity, diabetes, etc. When we talk about reversing aging - or, more accurately, the disease states associated with aging - we're talking about reregulating genes back to the healthy state people had when they were younger." Unlike most companies addressing the diseases associated with aging, Rejuvenate Bio tackles multiple cardiac, metabolic, and renal issues at once. "Based on the data we've seen from mice and dogs, we can reverse obesity, diabetes and heart disease."

Rejuvenate Bio has two therapies in its pipeline, RJB-01 and RJB-02, targeting the cardiac, metabolic and renal space. Both are delivered via adeno-associated viruses (AAV). The company expects RJB-01 to enter the clinic for humans in 2023, and also to be commercialized for animals that same year. RJB-01 targets overexpression of FGF21 and downregulation of TGFß1 via expression of sTGFßR2. Rejuvenate is developing it for heart failure. Research conducted by other companies shows that targeting these genes is also effective and safe for weight loss, diabetes, and tumor inhibition. The second therapy, RJB-02, is designed to treat osteoarthritis. It targets two genes - downregulation of TGFß1 via expression of sTGFßR2, and overexpression of αKlotho. The latter is associated with improving cognitive performance as well as protecting the heart and kidneys, and increasing insulin sensitivity.

Notably, the researchers combined two therapies into one to treat four age-related conditions. The results in mice showed "a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction, as well as a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. What's particularly exciting is that in mice, we showed we could halt progression of heart disease in its tracks despite the surgical tightening of the aorta." Similar results were seen in dogs, too.

The Supplement Industry is a Corrosive Presence, Lacking in Integrity

Senolytic therapies selectively destroy senescent cells, an important cause of inflammation and tissue dysfunction in older individuals. Removal of senescent cells via pharmacological means produces impressive demonstrations of rejuvenation in old mice, reversing the progression of many different age-related conditions. An intermittent or one-time high dose of fisetin has been tested as a senolytic in mice, and showed surprisingly good results. Why surprising? Because the similar compound quercetin does not appear to be meaningfully senolytic on its own. Quercetin improves the ability of the senolytic dasatinib to kill senescent cells; the combination of dasatinib and quercetin was the first pharmacological approach to senolytics tested in mice. The surprise is that fisetin on its own does just as well as dasatinib and quercetin at destroying senescent cells in mice, if the one study showing that outcome is to be taken at face value.

Fisetin is not a widely used supplement, relatively speaking, but it has been used for a good number of years, at doses 30-fold lower than the senolytic dose. What are the odds that an ability to produce sizable gains in human health in late life via an existing supplement was overlooked because a much higher dose was needed? We can debate the possible answers to that question, but it is better to wait for the results of an ongoing clinical trial of fisetin at these higher doses. One might also take a look at the Forever Healthy Foundation report that summarizes what is known of fisetin as a senolytic.

The supplement industry, of course, never waits on clinical trials. It is also an industry well practiced in the matter of lying by omission, distorting scientific findings, and selling hope and fraud rather than factual data. As might be expected given that history, one can presently find any number of groups selling "senolytic" supplements bearing small amounts of fisetin. Similarly for quercetin.

I'm going to point out Elysium Health as a particularly egregious example of this sort of thing, as it was founded by noted scientists in the aging research field, and continues to be associated with the Mayo Clinic, an institution presently carrying out clinical trials of senolytic therapies. If one looks at the latest marketing effort from Elysium that capitalizes on the efforts of researchers, in order to extract money from the credulous and the hopeful, you will find that they do not even say how much fisetin is included in their new product. They tout its link to clinical trials while deliberately obscuring the information needed to validate that the protocol offered is the same. Everyone involved in Elysium Health and its relationship with the research community should be ashamed of themselves.

This is a pointed example of the way in which the supplement industry is corrosive of integrity. I am all in favor of more of the safe senolytics being made more accessible to more people, with guidance on how to follow existing clinical trial programs. Even in advance of confirming human data, if a part of the supplement rollout is to produce equivalent data from a population of supplement users. The formal trial process is too slow, and good data can be obtained at less cost and more rapidly via other means. But there is a right way and a wrong way to go about this, and supplement industry companies near always choose the wrong way. This latest Elysium product adds little, and obscures much.

Elysium Health Announces the Launch of FORMAT Advanced Immune Support

Elysium Health, a leading life sciences company developing clinically validated health products based on advancements in aging research, today announced the launch of FORMAT, the first and only immune product to uniquely pair a daily immunomodulatory supplement with an intermittent senolytic complex to combat the effects of immune aging and provide complete immune support. The Senolytic Complex contains a powerful blend of quercetin and fisetin to help the body manage senescent cells, which supports healthy immune function and combats immunosenescence.


We now have access to substances called senolytics that, when administered on an intermittent basis, help to clear these problematic cells, supporting healthy immune function and helping the body respond to immunosenescence. Format incorporates micronutrients - necessary for baseline immune function - and pairs them with powerful senolytic compounds to keep your immune system functioning optimally. The formulation of Format's Senolytic Complex is based on research led by James Kirkland, M.D., Ph.D., Elysium Scientific Advisory Board member and director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic. This research has shown that senolytics are effective when administered intermittently.

Towards a Small Molecule Approach to Thymic Regeneration

The thymus is vital to a sustained and functional immune system. Thymocytes generated in the bone marrow migrate to the thymus, where a complex process of maturation and selection takes place, turning the thymocytes into T cells of the adaptive immune system. T cells must be capable of recognizing and reacting to pathogens and cancerous cells, without mistakenly attacking any of the normal systems of the body and its diverse cell population. That risk of self-immunity is the price of an adaptive immune system. The wide range of autoimmune conditions observed in the human population demonstrates that evolution does not produce infallible mechanisms.

The thymus atrophies with age, the active tissue replaced with fat. This reduces the supply of T cells, and in the absence of reinforcements the adaptive immune system relies increasingly on replication of peripheral immune cells to maintain its population. This leads to an aged immune system consisting of ever more harmful, senescent, exhausted, or otherwise problematic T cells. It is a sizable contribution to the age-related decline of immune function into chronic inflammation and incapacity.

There are many possible approaches to regeneration of the thymus, all of which have their issues. The thymus is a small, deep organ, which makes it hard to deliver therapies in a high enough dose without direct injection, and direct injection of that nature is probably too risky for widespread use. Mortality rates for similar procedures are around 0.1 to 0.2%. Several genes (e.g. FOXN1), recombinant proteins (e.g. growth hormone, KGF), and inhibitors (of androgens) would probably work very well to regrow the human thymus if the therapy could be delivered only to the thymus. Of these, only growth hormone can be used systemically at a reasonable cost-benefit calculation, as in the Intervene Immune protocol, but even then growth hormone isn't a treatment to be taken lightly.

Cell therapies and implantation of tissue engineered thymus organoids are presently the only obvious ways to work around the delivery issues. Several types of cell naturally home to the thymus, and researchers have demonstrated thymic regrowth in mice via delivery of such cells. It is plausible to consider the manufacture of universal cell lines that can be cost-effectively used in any patient; work on universal cells has yet to reach clinical approval, but it is quite advanced, undertaken by a number of large companies in the biotech industry. On the tissue engineering side of the fence, the company Lygenesis is built on research showing that thymus organoids can be implanted into lymph nodes, where they function in the same way a a normal thymus does. Building such organoids is presently an expensive process requiring donor tissue, however, and surgery, even minor surgery, is never cheap.

Several research groups are in search of a small molecule approach to spurring thymic regrowth, and have been for some years now. Small molecules have a different set of issues in comparison to the potential therapies noted above, in that what is known of the regulatory systems governing thymic growth does not yet present good, distinct targets. The thymus is an epithelial tissue, like the lining of the throat and intestines. As work on KGF demonstrates, there are unpleasant side-effects that attend the systemic delivery of signals to tell all epithelial tissue to grow. The path to a small molecule drug for thymus growth, if such a thing can be made, is to first search for a layer of regulation that is unique to the thymus. That is the goal of the research group responsible for today's materials.

New study identifies molecular players in 'dead man's switch' that triggers key immune organ's regeneration after damage

Prior to the current study, researchers had sketched the rough outlines of the thymus' renewal processes. This included identifying molecules that orchestrated two separate regenerative pathways (one triggered by a molecule called IL-22, and another by Bmp-4), and showing that it is the damage itself that triggers the thymus to renew. They'd also discovered that damage to the thymus sparks its regeneration by temporarily destroying a normal thymic developmental process.

T cells developing in the thymus undergo a rigorous "education" process that ensures that we aren't stuck with a lot of mature T cells that either can't recognize any signs of disease, or are primed to attack our healthy tissue instead of infected cells. Most T cells don't make the cut and get weeded out, dying by the thousands. Prior work suggested that dead and dying T cells acted as a brake on regeneration. When damage to the thymus wipes out T cells - surviving and dying alike - this brake is removed, and renewal mechanisms roar in to fill the void. Though researchers knew that dying T cells somehow acted as a brake to keep IL-22 and Bmp-4 - and thymic regeneration - suppressed, they didn't know how. Outlining the molecules that made up this sensor and suppressor system would reveal potential targets they could manipulate to promote regeneration.

The cells that help the thymus refill itself with T cells aren't T cells themselves, but accessory cells that support young T cells as they clear - or miss - their developmental hurdles. Researchers found that it's these accessory cells that sense dying T cells. They then outlined the molecular relays that lead from thymic damage to Bmp-4 and IL-22 (which activate thymus regeneration), identifying several key molecules along the way. Then, the researchers tested whether they could intervene. Researchers assessed whether blocking one of the players, called Rac1, (thereby boosting IL-22 and Bmp-4) helps improve thymic function after damage. They treated mice with an experimental Rac1 inhibitor after exposing them to radiation (similar to the thymus-blasting regimen that patients receive before bone marrow transplant). Mice treated with the Rac1 inhibitor produced more T cells than either untreated mice or treated mice that lacked a molecule in the T cell-death sensing pathway.

Perhaps the biggest hurdle right now is the lack of a Rac1 inhibitor available for clinical use. But researchers are hopeful; molecules related to Rac1, collectively called Rho GTPases, have been implicated in many diseases, and are an active area of investigation by pharmaceutical companies. "To move it forward, it's really going to require a drug itself. And that's where we're at, at the moment, trying to develop compounds that could be used clinically."

Extra Thymi and Lesser Thymic Involution with Age in Long-Lived Naked Mole-Rats

Naked mole-rats show little decline of function until late life, are highly resistant to cancer, and live nine times longer than similarly sized rodent species. An important aspect of immune system aging in mammals is the atrophy of the thymus. Thymocytes created in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. As active thymic tissue is replaced with fat, in the process of thymic involution, this supply of T cells declines. Absent reinforcements, the T cell population of the body becomes ever more damaged, malfunctioning, exhausted, and senescent. Researchers here show that not only do naked mole-rats have much delayed thymic involution, but they also exhibit the presence of multiple thymi.

Here, we provide the first characterization of the naked mole rat (NMR) thymus. We discovered that naked mole rats have an additional pair of cervical thymi. This is an unexpected finding as mammals, including humans and mice, as a rule, have only one bilateral thymus. Cervical thymi can occasionally be detected in mice, but their frequency is rare and they have unilateral appearance. Similarly, rare ectopic cervical human thymi had been reported in children. In contrast, cervical thymi are a principal component of NMR ontogenesis. Interestingly, among vertebrates, chickens have seven, sharks five, and amphibians three thymi. It is tempting to speculate that the presence of additional thymi in the naked mole rat may contribute to prolonged maintenance of immune function during their lifespan.

We provide evidence for a delay of thymic involution in naked mole rats beyond the 1st decade of their lifespan. Age-associated marker expression and thymic cell composition remained at the level of neonates. The absence of thymic involution up to midlife is unprecedented in mammals. This would translate into similar or even slightly heightened thymic weights and cell counts for humans in their 30s.

Thymic involution decreases output of naive T cells and reduces the ability to mount protective responses against new antigens. In naked mole rats, we did not see thymic involution in animals older than 10 years old, while markers for thymic function and development, AIRE and FOXN1, were maintained at neonatal levels. Furthermore, the reduction of early T-cell progenitors accompanying age-related lymphoid decline did not manifest in naked mole rats, arguing that their intrinsic myeloid bias in the marrow does not predispose hematopoiesis toward less lymphoid commitment. However, naked mole rats are not immortal and do show frailty in old age. Therefore, an eventual decline in thymic cellularity and immune function is to be anticipated, albeit delayed as opposed to the lifelong steady decline in humans and mice.

Earlier Hypertension Correlates with Smaller Later Brain Volume and Raised Risk of Dementia

The increased blood pressure of hypertension causes structural damage to delicate tissues throughout the body, particularly in the brain. Beyond the matter of an increased pace of rupture of capillaries, killing tiny volumes of brain tissue, the blood-brain barrier is disrupted by pressure damage, allowing unwanted molecules and cells into the brain to provoke chronic inflammation and disruption of function. Blood pressure is so influential on health that lowering blood pressure via antihypertensive medication, an approach that does not in any way address the underlying causes of the problem, produces a reduction in mortality that is in the same ballpark as that resulting from exercise programs.

Individuals who are diagnosed with high blood pressure at ages 35-44 had smaller brain size and were more likely to develop dementia compared to people who had normal blood pressure, according to new research. Hypertension is very common in middle-aged people (45-64 years), and early onset high blood pressure is becoming more common. Although the association among hypertension, brain health, and dementia in later life has been well-established, it was unknown how age at onset of hypertension may affect this association. If this is proven, it would provide some important evidence to suggest earlier intervention to delay the onset of hypertension, which may, in turn, be beneficial in preventing dementia.

The researchers analyzed data from participants in the UK Biobank, a large database containing detailed anonymous health information of about half a million volunteer participants in the United Kingdom. To determine brain changes, they compared magnetic resonance imaging (MRI) measurements of brain volume between two large groups of adults in the database: 11,399 people with high blood pressure diagnosed at different ages (younger than age 35; 35-44 years; and 45-54 years), and 11,399 participants who did not have high blood pressure, matched for age and multiple health-related variables. Participants entered the databank between 2006 and 2010, and they had MRI brain scans between 2014 and 2019.

In each diagnostic age category (from 35 to 54), the total brain volume was smaller in people diagnosed with high blood pressure, and the brain volume of several regions were also smaller compared to the participants who did not have high blood pressure. Hypertension diagnosed before age 35 was associated with the largest reductions in brain volume compared with controls. Among people with normal blood pressure readings at the time of their MRI scans, those who were previously diagnosed with hypertension at ages younger than 35 years old had smaller total brain volume compared to people with normal blood pressure who had never been diagnosed with hypertension.

The risk of dementia from any cause was significantly higher (61%) in people diagnosed with high blood pressure between the ages of 35 and 44 compared to participants who did not have high blood pressure. The risk of vascular dementia (a common form of dementia resulting from impaired blood flow to parts of the brain, as might happen after one or more small strokes) was 45% higher in the adults diagnosed with hypertension between ages 45-54 and 69% higher in those diagnosed between ages 35-44, compared to participants of the same age without high blood pressure.

Exploring Mechanisms by Which Exercise Slows Cancer Progression

Cancer patients who exercise tend to do better than those who do not. While one cannot escape an established cancer via physical activity, one can modestly slow it down, it appears. Researchers here explore some of the mechanisms by which exercise can achieve this goal, focusing on muscle tissue signaling that both slows cancer cell growth and provokes greater immune system activity. The usual path forward for this sort of research, given a large enough effect size to be interesting, is to try to find a way to deliver additional signal proteins as a form of treatment. This might be achieved directly using recombinant protein therapy, or via some form of small molecule drug that upregulates signal protein expression. In either case, that is a road of some years from present understanding to eventual therapy, and it isn't at all clear that the size of the effect justifies that effort.

Exercise causes muscles to secrete proteins called myokines. Researchers have learned these myokines can suppress tumour growth and even help actively fight cancerous cells. A clinical trial saw obese prostate cancer patients undergo regular exercise training for 12 weeks, giving blood samples before and after the exercise program. Researchers then took the samples and applied them directly onto living prostate cancer cells.

"The patients' levels of anti-cancer myokines increased in the three months. When we took their pre-exercise blood and their post-exercise blood and placed it over living prostate cancer cells, we saw a significant suppression of the growth of those cells from the post-training blood. That's quite substantial indicating chronic exercise creates a cancer suppressive environment in the body."

while myokines could signal cancer cells to grow slower - or stop completely - they were unable to kill the cells by themselves. However, myokines can team up with other cells in the blood to actively fight cancer. "Myokines in and of themselves don't signal the cells to die. But they do signal our immune cells - T-cells - to attack and kill the cancer cells."

Greater Expression of Mitochondrial Base Excision Repair Enzymes in Longer-Lived Mammalian Species

The hundreds of mitochondria present in every cell are critical to cell function. As the descendants of ancient symbiotic bacteria, mitochondria have their own remnant DNA, separate from the chromosomal genomic DNA present in the cell nucleus. Both sorts of DNA suffer similar forms of mutational damage and are attended by broadly similar repair mechanisms, but nuclear DNA is by far the better protected and maintained of the two. Some forms of mitochondrial DNA mutation, particularly the deletion of genes important to the electron transport chain, are thought to confer both dysfunction and competitive advantages to mitochondria, leading to a cell overtaken by broken mitochondria, exporting toxic reactive molecules into surrounding tissue. This may be important in aging, and in support of that proposition, researchers here find that longer lived mammalian species have a greater capacity for some forms of mitochondrial DNA repair.

Is the DNA repair of endogenous damage higher in long-lived animals? When base excision repair (BER) of genomic DNA was measured in four organs including heart and brain it was found not significantly changed or even decreased (instead of increased) in longer-lived caloric restricted mice. Moreover, comparative studies in brain and liver of 15 mammalian and avian species have shown that repair of genomic DNA endogenous oxidative damage by BER in nuclear fractions does not correlate with longevity or, more frequently, is lower (instead of higher) in tissues of long-lived mammals when compared to short-lived ones.

BER plays an important role in repairing oxidative damage to DNA, but these results might indicate that genomic (almost all nuclear) BER does not play a key role in longevity extension. The negative correlation of genomic DNA BER with longevity is analogous to what was previously found for the endogenous total cellular antioxidant enzymes CuZn SOD, catalase, glutathione peroxidase, and glutathione reductase, as well as reduced glutathione, which most generally negatively correlate, and in some cases do not significantly correlate with longevity in mammals and vertebrates.

The likely evolutionary explanation for this is that the mitochondrial ROS production rate (mitROSp) is also lower in long-lived than in short-lived animals. Since the mitochondria of long-lived animal species produce less H2O2 to the cytosol, they would also need less total cell endogenous antioxidants and less nuclear DNA repair systems. Endogenous total cell antioxidants and DNA repair enzymes are transitorily induced, when needed, to come back again to low levels when episodic increases in oxidative stress have been overcome. In this way, cells save much energy, which otherwise would be invested in the protein synthesis needed to continuously maintain high levels of cellular antioxidants and nuclear DNA repair enzymes when they are not needed at such high levels.

That is the situation concerning BER in nuclear DNA, but what occurs in the case of mitochondrial BER (mitBER)? MitBER had never been measured in species with different longevities, and we hypothesized that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus recently measured activities and/or protein levels of various mitBER enzymes including DNA glycosylases, NTHL1 and NEIL2, and APE endonuclease in mitochondrial liver and heart fractions from eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between mitBER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitDNA of long-lived species, not observed for nuclear DNA, can be due to the combination of a low rate of damage generation (low mitROSp) and a high level of mitDNA repair (by mitBER) in these slowly aging animals.

Engineered B Cells as an Approach to Cancer Therapy

Engineered T cells are the dominant form of cell therapy for cancer at the present time, an approach that has achieved considerable success, and remains actively under further development. T cells can attack cancer cells directly, given the right tools to recognize those cells and overcome the various immunosuppressive mechanisms deployed by cancerous tissue. There are other approaches to rousing the immune system to action, however, such as focusing on B cells. B cells carry out a variety of roles that are important in the coordination of the immune response, in providing targets for other cells to attack, and rousing those cells to action. Thus it should be possible to engineer B cells to be much more effective in the context of cancer, improving the overall immune response.

Nowadays, cancers still represent a significant health burden, accounting for around 10 million deaths per year, due to ageing populations and inefficient treatments for some refractory cancers. Immunotherapy strategies that modulate the patient's immune system have emerged as good treatment options. Among them, the adoptive transfer of B cells selected ex vivo showed promising results, with a reduction in tumor growth in several cancer mouse models, often associated with antitumoral immune responses. Aside from the benefits of their intrinsic properties, including antigen presentation, antibody secretion, homing, and long-term persistence, B cells can be modified prior to reinfusion to increase their therapeutic role.

For instance, B cells have been modified mainly to boost their immuno-stimulatory activation potential by forcing the expression of costimulatory ligands using defined culture conditions or gene insertion. Moreover, tumor-specific antigen presentation by infused B cells has been increased by ex vivo antigen loading (peptides, RNA, DNA, virus) or by the sorting/ engineering of B cells with a B cell receptor specific to tumor antigens. Editing of the B cell receptor also rewires B cell specificity toward tumor antigens, and may trigger, upon antigen recognition, the secretion of antitumor antibodies by differentiated plasma cells that can then be recognized by other immune components or cells involved in tumor clearance by antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity for example.

With the expansion of gene editing methodologies, new strategies to reprogram immune cells with whole synthetic circuits are being explored: modified B cells can sense disease-specific biomarkers and, in response, trigger the expression of therapeutic molecules, such as molecules that counteract the tumoral immunosuppressive microenvironment. Such strategies remain in their infancy for implementation in B cells, but are likely to expand in the coming years.

Lithium Produces Mildly Positive Effects on Healthspan in Mice

The relationship between lithium intake and health is a topic of minor interest, in that no-one is going to be building a rejuvenation therapy on the basis of the mechanisms by which lithium may very modestly slow aging in short-lived species. There is some evidence for greater human life expectancy to occur in areas in which there is more lithium in the water supply, but this sort of geographical epidemiology is fraught with confounding factors relating to wealth, preferences, culture, and migration. As researchers note here, lithium has both a narrow therapeutic window and only small effects on healthspan in mice.

The anti-depressant and mood stabilizing effects of lithium were discovered the mid 20th century, and administration of lithium salts is still the first-line therapy for bipolar disorders. Lithium can also ameliorate pathology in animal models of neurodegeneration, through multiple molecular mechanisms, and has been proposed as a therapy for Alzheimer's disease. Suggesting that it may have a broader therapeutic range, lithium can also extend lifespan in fission yeast, C. elegans, and Drosophila, in the last by inhibition of GSK-3 and activation of the transcription factor NRF2. Human survival across 18 Japanese municipalities correlated with increased lithium level in drinking water. These findings suggest that conserved molecular responses to lithium treatment could improve health during ageing in mammals. In this study, we therefore analysed the influence of lithium treatment on lifespan and parameters of health during ageing in mice.

To determine the concentration of lithium suitable to be administered in a longitudinal ageing study, we first tested the effects of lithium chloride (LiCl) in doses from 0.01 to 2.79 g LiCl per kg chow. C57Bl/6J mice fed with 1.05-2.79 g/kg LiCL in the diet showed lithium plasma levels between 0.4 and 0.8 mM/l. While plasma levels to 0.4 and 0.8 mM/l are well tolerated by human patients, at doses above 1.44 g LiCl/kg, we observed an obvious dose-dependent polydipsia combined with a distinct polyuria, pointing towards a significant degree of kidney toxicity.

We therefore carried out life-long lithium treatment in the range from 0.02 to 1.05 g/kg diet. Administration to both sexes at doses of 0.02 and 0.05 g/kg starting at 3 months or 18 months of age did not affect lifespan. In an additional group, treatment of females with 0.1 g/kg starting at 19 months of age also had no significant effect. Treatment of male and female mice from an age of 3 months with 0.02 and 0.05 g/kg LiCl, and then switching late in life at 22 months to 0.5 and 1.05 g/kg, respectively, had no effect on male survival and reduced maximum lifespan of females (survival of last 20% of animals to die).

We assessed the effects of lithium on other age-related phenotypes of the mice. Decreased fat mass despite unaffected food consumption indicates an effect of lithium on lipid metabolism. Mice on the low doses of 0.02 and 0.05 g/kg LiCl administered from 3 months of age showed delayed age-related loss of glucose tolerance. In addition, male mice that were switched to 0.5 and 1.05 g/kg at 22 months, after being treated with 0.02 and 0.05 g/kg from an age of 18 months, respectively, showed significantly increased tolerance to glucose at ages over 26 months. Neither treatment improved glucose tolerance in females.

There was a dose-dependent increase in motor function on the rotarod in old males under LiCl treatment, possibly related to their lower body weight. Additionally, in 24-month-old Li2CO3-treated mice, both motor function on the rotarod and endurance on the treadmill were significantly increased in males, with no effect in females. Histopathological analysis of 2-year-old, Li2CO3-treated, C3B6F1 mice showed reduced age-related pathologies in the kidneys, with significantly decreased kidney inflammation (leukocyte infiltration) in both sexes, which in males coincided strongly with a reduction of glomerulopathy.

Considering the use of a broad range of well-tolerated lithium concentrations, different lithium salts and different mouse strains, we conclude that, in contrast to the findings in yeast, worms, and flies, lithium does not seem to be a promising candidate for geroprotection in humans. Although it caused mild improvements in body weight and composition, glucose tolerance and motor performance, these were largely confined to males and were not accompanied in either sex by increased lifespan.

Senescent Cells Hinder Fracture Repair, Rather than Helping as Might Be Expected

Regeneration might be thought of as a complex and highly coordinated interaction between stem cells, somatic cells, and senescent cells. Some small fraction of cells in the injured tissue become senescent, cease replication, and secrete pro-growth, pro-inflammatory factors. They are then removed by the immune system once their task is done, to prevent long-term disruption of tissue function by those same secretions. The problem of senescent cells in aging is entirely that this signaling for growth and inflammation, beneficial in the short term, becomes very harmful and disruptive to normal tissue function when present for the long term.

It was thought that senescent cells assist in wound healing throughout the body, based on evidence gathered largely from skin injuries. Here, however, researchers present evidence to show that senescent cells actually hinder fracture healing, and thus senolytic therapies to selectively destroy senescent cells may be beneficially applied to this sort of injury. This suggests that senescent cells may actively impede regeneration in other tissues as well.

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization.

Then, using a genetic mouse model containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.

The Rejuvenome Project Announces Collaboration with the Buck Institute

I recently noted the Astera Institute's Rejuvenome project. The work will be conducted in collaboration with the Buck Institute. It is a sizable proposal, to conduct large and rigorous mouse studies with the ultimate goal of testing combined interventions, a necessary activity that the research community and industry alike largely fail to carry out. This is a big problem in the field of aging, as aging is the outcome of a range of distinct processes of damage accumulation. Sizable degrees of rejuvenation or slowing of aging can in the long run only emerge from combinations of approaches, repairing or working around multiple forms of damage. Given this large gap in research and development, one that will never be filled by existing institutions, philanthropic efforts must step in to fill the gap.

Research on aging is at a critical inflection point, with breakthroughs in basic science and multiple compounds being tested in clinical trials. While the field is starting to have tools and treatments that target the biology of aging and improve health, a deep and fundamental understanding of how they work, and the models used to validate such findings, is still lacking. Further, because of vision, funding constraints, infrastructure limitations and other impediments, smaller projects are conducted independently of each other and there is little to no research into combination therapies, even though this will likely be the only avenue to achieving meaningful results.

"The Rejuvenome Project was launched to target these bottlenecks. We hope to do that by characterizing treatments and regimens, both established and newly invented, for which we have reason to believe improve health and longevity. The breadth and depth of this project centered around an unprecedentedly extensive and deep whole-body functional and multi-omic assay panel has the potential to redefine scientific understanding of how to best intervene in the aging process."

The Rejuvenome Project is expected to take approximately seven years to complete. All wet lab operations will be centered at the Buck while the dry lab computational aspects of the project will reside at the Astera Institute in Berkeley. "The Rejuvenome is the quintessential moonshot project in longevity. If we are successful it will provide the most complete picture ever of how best to intervene in aging and will produce powerful new avenues for drug development."

An Example of Senomorphic Drug Discovery

Senescent cell accumulation is a feature of aging, a growing imbalance between the rate of creation and rate of destruction. Senescent cells perform a number of useful tasks in the short-term, but when present for the long-term, their inflammatory secretions disrupt tissue function and contribute meaningfully to the onset and progression of age-related disease. A great many research groups are working towards the basis for therapies that can selectively destroy senescent cells (senolytics). Others are working on ways to prevent cells from becoming senescent, or suppress the worst of the bad behavior of existing senescent cells (senomorphics). The open access paper here is a representative example of the latter development process.

The senescence-associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro-inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence-associated diseases. Here, we identified a small molecule SR9009, a specific agonist of NR1D1/NR1D2, as a potent SASP suppressor in therapy-induced senescence (TIS) and oncogene-induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes.

We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation-induced and oncogene-induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence.

A Trial of the Senolytic Fisetin as a Treatment for Older SARS-CoV-2 Patients

Senolytic treatments are those that selectively destroy senescent cells, a form of intervention that has produced rejuvenation in older animals. A high dose of the flavonol fisetin is not yet proven to be usefully senolytic in humans, but has shown a surprising degree of efficacy in mice. The only senolytic therapy demonstrated to clear senescent cells in old humans is the dasatinib and quercetin combination. Quercetin itself, though similar to fisetin, does not appear to be usefully senolytic on its own. The paper here notes a clinical trial of fisetin for older COVID-19 patients. It is thought that the larger number of senescent cells present in older individuals contribute meaningfully to a greater susceptibility to the severe inflammatory events that are the cause of death in COVID-19. This is one of a number of trials of fisetin as a senolytic; we might hope that at least one of these studies reports on whether or not senescent cell burden is actually reduced in these patients, as was done in one of the dasatinib and quercetin trials.

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors.

Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality.

A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients.

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