Fight Aging! Newsletter, December 9th 2019

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  • The Catalytic Antibody Approach to Amyloid Aggregation
  • This Giving Tuesday, Support Rejuvenation Research at the SENS Research Foundation
  • The Prospects for Restoring Neurogenesis in the Aging Brain
  • Mesodermal Progenitor Cells Enable the Generation of Vascularized Organoids
  • Tryptophan Metabolism and Inflammaging
  • More Aggressive Control of Blood Pressure Modestly Extends Life in Older People
  • Potentially Significant Gut Microbiome Changes Occur in Younger Adult Life
  • IL-15 as an Exercise Mimetic that Improves Wound Healing in Old Mice
  • Fibrosis as an Important Contributing Cause of Atrial Fibrillation
  • A Demonstration of Small Molecule Inhibition of Tau Aggregation
  • Discovering New Mechanisms of Action for Metformin
  • On Making Philanthropy in Support of Rejuvenation Research Attractive to Investors
  • The Latest on Cellular Senescence in Type 2 Diabetes
  • Evidence for Exercise to Slow Cognitive Decline
  • Reviewing the DNA Damage Response in Aging

The Catalytic Antibody Approach to Amyloid Aggregation

Today's paper is authored by the Covalent Bioscience science team, and is an overview of the science underlying their catalytic antibody (or catabody) approach to clearing amyloids of various sorts from aged tissues. It isn't open access, unfortunately, but the paper is, as usual, available to the world thanks to the ethical civil disobedience of the Sci-Hub team. Amyloids are solid deposits formed by one of the very small number of proteins in the body that can become misfolded or otherwise altered in ways that cause other molecules of the same protein to also alter in the same way. These errant proteins aggregate into structures that are surrounded by a halo of damaging biochemistry that degrades cell function or kills cells, and, once started, this aggregation can spread through tissues over time.

The Covalent Bioscience team believes that natural catalytic antibodies are the primary way by which our biochemistry tries to clear out amyloids - but evidently, amyloid generation overwhelms this mechanism as aging progresses. Catalytic antibodies act as catalysts for reactions that break down amyloids. Because one catalytic antibody can do this for many amyloid molecules, they have the potential to be a highly efficient basis for therapy. The process of development is to identify natural catalytic antibodies specific to a target amyloid, improve on their structure and function, establish ways to manufacture these improved versions at scale, and then deliver them in large numbers as a therapy.

Covalent Bioscience is a fair way into the preclinical development phase of this project for catabodies targeting transthyretin amyloid, a cause of heart disease and other conditions, and the amyloid-β associated with the early stages of Alzheimer's disease. The paper is an interesting read, and recommended if you'd like greater insight into catabodies as a novel form of therapy to remove misfolded proteins.

Catalytic Antibody (Catabody) Platform for Age-Associated Amyloid Disease: From Heisenberg's Uncertainty Principle to the Verge of Medical Interventions

Thirty seven proteins misfold into particulate and soluble aggregates. The misfolding process is accelerated by age-associated metabolic disturbances, for example, increased generation of advanced glycation end products and lipid peroxidation end products. Misfolded self-protein aggregates are a significant cause of aging, exemplified by appearance of lumbar spinal stenosis and carpal tunnel syndrome due to misfolded transthyretin in 40-50% of humans older than 50 years age and cardiac myopathy at a later age. About 15-20% of humans show at least mild cognitive impairment due to Alzheimer disease, thought to be triggered by misfolded amyloid β aggregates starting around age 65 years.

Our studies suggest that specific, constitutively produced catabodies are the primary proteostatic mediators in the blood of humans that destroy the disease-causing misfolded self-protein aggregates. In contrast, text-book portrayals of humoral immunity focus on IgG class antibodies that mature within days to weeks following stimulation with the foreign (non-self) antigens. The observed catabody properties display clear departures from classical immunology rules. Our perspective of constitutive catabodies specific for the disease-causing misfolded self-proteins is conditioned by the organismal survival requirements during Darwinian evolution. As the problem of protein misfolding is an intrinsic organismal weakness that is even more ancient than the threat of extinction due to the external microbes, eliminating amyloid disease at an early age can safely be assumed to serve as a strong selective pressure for evolving a constitutive immune defense against the misfolded proteins, i.e., the specific germline gene-encoded catabodies.

Catabodies outperformed ordinary antibodies in two significant aspects. By definition, a catalyst is re-used again and again to inactivate and destroy large quantities of the harmful target. First, we proved in side-by-side tests that a small catabody amount permanently removes the target with efficacy far superior to an ordinary antibody (which can only bind reversibly to the target on a 1:1 basis). Human IgM catabodies selectively destroyed misfolded but not normally folded transthyretin into non-aggregable fragments without potential for initiating or sustaining systemic amyloid disease. Likewise, human catabody fragments digested amyloid-β into non-toxic and non-aggregable fragments without potential for initiating or sustaining Alzheimer's disease. Second, while ordinary antibodies form stable immune complexes that inevitably induce inflammation, the catabody-substrate complexes are too transient to activate inflammatory cells. Catabodies are particularly valuable if large amounts of the target are to be removed, as is required for effectively treating amyloid diseases. In such diseases, the inflammatory damage induced by an ordinary antibody will be so great that the favorable amyloid removal effect is essentially canceled out.

Many things go wrong in human aging, and if humans live long enough something or the other invariably goes wrong. The phenomenon of constitutive catabodies is not limited to the misfolded transthyretin and amyloid-β disease-causing proteins. We identified catabodies to additional amyloid-forming proteins (misfolded tau, immunoglobulin light chains). Indeed, the value of the Catabody Platform likely extends to virtually any of the innumerable proteins that contribute directly or indirectly in disease and damage to various organ systems in aging, including the protein targets involved in increased susceptibility of humans to microbial infections and autoimmune, neurological, cardiovascular, and neoplastic disease. Specific catabodies can be generated on-demand either from the constitutive or immunogen-induced antibody repertoires.

We subscribe to the view that preventing age-associated dysfunctional processes before they have caused substantial damage is the preferred medical strategy for prolonging healthy lives. Prophylactic vaccines against infectious microbes have improved public health enormously. We suggest that lessons from our vaccine approach for microbes are valuable in developing safe and efficacious anti-amyloid longevity vaccines. The central requirements for such longevity vaccines is inducing long-lasting synthesis of catabodies with epitope specificity suitable for destroying the disease-causing misfolded self-proteins without interfering in the physiological functions of the properly folded conformations of these proteins.

Our vision is to bypass the mechanism-based limitations of ordinary antibodies and vaccines for fulfilling important unmet medical needs: (a) Intrinsic inability of ordinary antibodies to bind the target with stoichiometry greater than 1:1; (b) The inevitable activation of inflammatory pathways upon antibody-target binding that not only cause unacceptable side effects but also reduce efficacy through functional antagonism pathways, as seen in numerous failed trials of antibodies in patients with Alzheimer's disease; and (c) Failure of ordinary vaccines to induce protective immunity to certain protein epitopes because of immune check-point suppressor mechanisms.

The lead products generated from our Catabody Platform have not shown these limitations. Success in early stage human trials of any one lead catabody will make the entire underlying technology more attractive, thus encouraging development of additional catabodies and vaccines for new disease targets. For instance, transthyretin amyloid disease and Alzheimer's disease are but 2 of 56 amyloid diseases caused by misfolded proteins. Our findings suggest that destruction of misfolded proteins by catabodies extends beyond the targets described in this article. The Catabody Platform is enabled to utilize both innate immunity and immunogen-induced acquired immunity for generating catabodies to virtually any target protein.

This Giving Tuesday, Support Rejuvenation Research at the SENS Research Foundation

It is Giving Tuesday today, a prompt for each of to think about the change that we would like to see happen in the world, and then do our parts in making it happen. We can all be philanthropists, we can all support the projects that we believe will improve the human condition. In the sciences, it is largely exactly this sort of motivated philanthropy that funds the most important progress, that which takes place at the cutting edge of research. Public funding for research is near always only awarded after the discovery is made, after the proof of principle is demonstrated. Commercial funding tends to arrive later still. The vital work of generating that proof of principle is, in practice, funded through donations made to researchers and research institutions.

A good example is the progress towards real, working rejuvenation therapies, those based on the SENS model of periodic repair of cell and tissue damage, that has been generated by the SENS Research Foundation and Methuselah Foundation before it. These projects have been near entirely funded by our community over the years, and have led to multiple lines of work making the leap from laboratory to startup company. These are our success stories: we all helped to make this happen by choosing to donate in support of the SENS rejuvenation research projects. We have made a start, but there are still important projects to assist.

The SENS Research Foundation year end fundraiser is running, and this Giving Tuesday give some thought to supporting the work of the foundation on bringing rejuvenation therapies to the clinic. What sort of future do you want to see? One in which we are ever less troubled by the suffering and disease of aging? Then donate to the SENS Research Foundation; it remains the most effective organization in this field when it comes to making progress in the fundamental research of human rejuvenation, advancing the most promising programs from laboratory to clinical development.

Giving Tuesday is a global generosity movement, giving power to individuals for the transformation of their communities and to create a global impact. The idea is simple: do good. Started in 2012, this idea has inspired millions of people to give, collaborate, and celebrate generosity. This year, maximize the good your gift can do by donating to SENS Research Foundation.

For this year's #GivingTuesday event on December 3rd, 2019, we're delighted to announce matching challenges from long-term supporters Christophe Cornuejols and David Chambers. Christophe will match the first 20,000 donated at any time on Giving Tuesday, and David will match the first 10,000. Thanks to their combined generosity, the first 10,000 given will be tripled, and the second 10,000 will be doubled!

Chrisophe said that "it is my strong belief that we are the first generation in history which has the capability to decide to be the last generation to die of aging or be the first not to. The evolution of science and technology gives us that choice. Either we invest in research in this area now, and gain 20, 30, 200 years of healthy life, or we leave it to a future generation. It's just up to us to decide."

David notes that "I've known Aubrey for fifteen years, and witnessed him over that time energise a new field of scientific endeavour. I'm convinced that donations to SRF will realise great improvements in human wellbeing."

The Prospects for Restoring Neurogenesis in the Aging Brain

Today's open access paper is a review of potential approaches that might be used as a basis for therapies to restore a more youthful level of neurogenesis in the aging mammalian brain. Neurogenesis is the process by which new neurons are created by neural stem cell populations and then integrated into neural networks. In adults, neurogenesis is essential to memory, learning, and the limited degree of regeneration that the brain is capable of enacting. Unfortunately, the supply of new neurons declines with age as the underlying stem cells become ever less active. Beyond making the aging brain more resilient, methods of increasing neurogenesis may prove to be enhancement therapies capable of improving cognitive function even in young people.

Any discussion of adult neurogenesis must note the present debate over whether or not it in fact does take place in humans in the same way as it does in mice. It was only in the 1990s that neurogenesis was discovered to take place in some portions of the adult mouse brain, and since then near all work on neurogenesis in general, as well on changes in neurogenesis with age, has focused on mice, given the costs and difficulties inherent in studying human brains and brain tissue. This became a growing concern, careful human studies were undertaken, and in the past few years rigorous evidence has been presented on both sides of the question of adult human neurogenesis, both ruling it out, and demonstrating that it does take place. Considerable debate has taken place over the technical details of these studies and the underlying processes of neurogenesis. Insofar as there is a present weight of evidence, it appears to lean towards the conclusion that humans do in fact exhibit adult neurogenesis.

Rejuvenating subventricular zone neurogenesis in the aging brain

Adult neurogenesis is the generation of new neurons from neural stem cells (NSCs). NSCs are known for their hallmark characteristics of long-term self-renewal and differentiation into neurons and glia. While many noncanonical sites of neurogenesis have been observed in the mammalian brain, the two main stem cell niches studied are the subventricular zone (SVZ) located along the walls of lateral ventricles (LV) and subgranular zone (SGZ) in the hippocampus. The largest pool of NSCs in rodents lies in the SVZ, where the majority of NSCs are quiescent (qNSCs). These qNSCs undergo activation (aNSC) and proliferate to produce transit amplifying cells (TACs). TACs rapidly proliferate and then differentiate into neuroblasts that migrate in chains along the rostral migratory stream (RMS) to the olfactory bulb (OB) and become synaptically integrated into the existing circuitry.

Neurogenesis in the SVZ results in the functional integration of neurons in the OB. This has been shown to be important in olfactory behavior such as memory and scent/pheromone discrimination. In addition, brain injury, in the form of ischemic stroke, induces NSC proliferation and production of neuroblasts (NBs). These NBs migrate to the site of injury to differentiate into astrocytes and neurons that synaptically integrate into the peri-infarct cortex. Blockade of neuroblast migration results in increased lesion size and worsened behavioral outcomes as SVZ-derived neurons with synaptic function are critical to stroke recovery. Additionally, post-stroke neurogenesis is plastic and can be increased and directed by overuse behavior that mimics current human neurorehabilitation therapies. During aging, neurogenesis is reduced, which contributes to declines in olfactory memory and repair.

Multiple strategies to rejuvenate neurogenesis have come from experiments utilizing blood/plasma exchange between young and aged rodents. Landmark studies utilizing heterochronic parabiosis, where a young and aged mouse are connected surgically to share circulation, showed that young circulating factors can rejuvenate neurogenesis in aged mice vice versa with old circulating factors young mice. The field has since made further progress by identification of circulating rejuvenation factors of NSCs in the SVZ and hippocampus that include GDF11 and TIMP2, as well as the pro-aging factors CCL11, β2-microglobulin, TGF-β, and recently VCAM1.

The dietary interventions caloric restriction (CR) (10-40% reduction in caloric intake) and the fasting mimicking diet (FMD) (50-90% reduction in caloric intake for 4 days twice a month) are perhaps the most robust, pleiotropic, and conserved methods of longevity extension and rejuvenation. In a mouse model of caloric restriction starting at 14-weeks of age, the number of NB and new neurons in the OB were preserved in the aged (12-months to 18-months) and comparable to levels of ad libitum fed young (six-month) mice. This preservation of neurogenesis resulted in olfactory memory in aged mice that was similar to young (six-month) mice.

The two top drugs that have emerged from CR research are rapamycin and metformin, which act primarily through inhibition of the mTOR and activation of the AMPK (downstream inhibition of mTOR) pathways. However, other studies suggest that mTOR signaling is a mediator of TAC proliferation since rapamycin treatment decreases the number of TACs in two-month old mice and mTOR activation decreases with age, concomitant with proliferation. Metformin has been shown to enhance proliferation in the young (three-month) SVZ, but despite interest in using metformin to ameliorate aging phenotypes, research with this drug in the aging SVZ is lacking.

Multiple lines of evidence now point towards an increased age-dependent inflammatory environment within the SVZ. A major source of this inflammation originates from aged microglia and should be a central target for inflammation reduction in future studies. Having identified the neurogenic-inhibiting contribution of aged microglia to NSC proliferation, researchers fed 8-month old mice the anti-inflammatory drug HCT1026. This treatment restored redox/inflammatory balance to the niche, and substantially increased neurogenesis. Increase in senescent cell burden in the aging SVZ has been found in 12-18 month old mice. Avoidance of the senescence program was achieved with p16INK41-/- mice aged to 15-19 months that partially rescued OB neurogenesis. A recent study showed that obesity is associated with increased senescence and reduced neuroblasts in the SVZ of middle-aged (10-13 months) mice and clearance of senescent cells partially rescued the number of neural precursors. Thus, removal of senescent cells in elderly mice, especially using treatments such as Dasatinib + Quercetin that have been used in clinical trials, appear to be favorable routes to rejuvenate neurogenesis but are in need of further study in aged animals to determine long term effects.

The studies gathered here present compelling evidence that aging of the SVZ niche is not a one-way street. Instead, the aging process is not only delayable through early interventions such as CR, but is also reversible by way of systemic interventions started late in life. The possibility of rejuvenation not only sheds light on the mechanisms of NSC aging, but is also an appealing therapeutic avenue for the rapidly increasing elderly human population.

Mesodermal Progenitor Cells Enable the Generation of Vascularized Organoids

Researchers have made considerable progress in the construction of small, functional tissue sections called organoids over the past decade, enabled by a combination of better understanding the mechanisms involved in regeneration and embryonic development of tissues, advances in 3-D bioprinting, guidance of cell behavior via appropriate provision of signal molecules, and the generation of environments that mimic an existing tissue environment. Every tissue requires its own specific recipe of signals and environment in order to form a functional organoid, but researchers have demonstrated the manufacture of organoids for liver, kidney, lung, and thymus, among others.

Organoids are tiny, usually a millimeter or two in size. They are a stepping stone to the generation of patient matched replacement organs on demand, given a cell sample as a starting point. Ever since the first organoids were generated, however, the blocking challenge to scaling up engineered tissue in size has been the inability to generate organoids that incorporate functional blood vessel networks. In cross-sections of natural tissues, several hundred capillaries pass through every square millimeter. Absent this microvasculature, blood (and thus the necessary oxygen and nutrients for cell survival) cannot perfuse through more than a few millimeters into tissues.

Producing vasculature in engineered tissues has proven to be challenging. That it is so challenging is why considerable effort has gone towards establishing decellularization of donor organs and xenotransplantation of genetically engineered pig organs as a basis for expanding the pool of organs available for transplantation. Of late some progress has been made on methods of 3-D printing organoids that contain an initial vasculature that is dense enough to sustain the tissue, albeit short of the natural capillary density. Today's open access paper describes an example of the opposite approach, which is to find a suitable combination of cells, signals, and environment that causes a microvasculature to form within the organoid as it grows.

Generation of complex human organoid models including vascular networks by incorporation of mesodermal progenitor cells

Organoids derived from human induced pluripotent stem cells (hiPSCs) are state of the art cell culture models to study mechanisms of development and disease. The establishment of different tissue models such as intestinal, liver, cerebral, kidney, and lung organoids was published within the last years. These organoids recapitulate the development of epithelial structures in a fascinating manner. However, they remain incomplete as vasculature, stromal components, and tissue resident immune cells are mostly lacking. All these cell types derive from mesenchymal tissue and it is well known that epithelial-mesenchymal interactions play a fundamental role during tissue development.

Recent publications addressed this issue, especially with regard to organoid vascularization. Researchers demonstrated that human blood vessels self-organize and can be grown in vitro. In order to vascularize cerebral organoids, others added endothelial cells to the system. But blood vessels are more complex than an endothelial tube. Larger vessels consist of multiple layers that contain cell types such as endothelial and smooth muscle cells, while even small capillaries rely on the support of pericytes and a basal lamina. Other groups generated vascularized neural organoids consisting of blood vessels and microglia. However, in these cases, the heterologous vessels as well as microglia are host derived and invade the neural organoid after transplantation.

We propose that the directed incorporation of mesodermal progenitor cells (MPCs) into organoids will overcome the aforementioned limitations. In order to demonstrate the feasibility of the method, we generated complex human tumor as well as neural organoids. We show that the formed blood vessels display a hierarchic organization and mural cells are assembled into the vessel wall. Moreover, we demonstrate a typical blood vessel ultrastructure including endothelial cell-cell junctions, a basement membrane as well as luminal caveolae and microvesicles. We observe a high plasticity in the endothelial network, which expands, while the organoids grow and is responsive to anti-angiogenic compounds and pro-angiogenic conditions such as hypoxia. We show that vessels within tumor organoids connect to host vessels following transplantation.

Tryptophan Metabolism and Inflammaging

Today's open access research on tryptophan and its role in age-related immune dysfunction is particularly interesting in the context of ongoing research into the changes that take place in gut microbiota with age. Other recent work has examined the way in which tryptophan production by gut microbes declines precipitously with age, as this is one of a number of compounds produced by bacteria, such as butyrate, indole, and proprionate, that are influential on long term health. It is a slow process, but researchers are uncovering the specific mechanisms linking age-related changes in gut microbe populations with declining health. The overall size of effect of gut microbes on heath might be in the same ballpark as that of exercise, but this is only suggested by the evidence to date, not rigorously established.

Given detrimental changes in gut microbes, declining production of beneficial compounds, and a rise in chronic inflammation due to a rise in the presence of harmful microbes, what might be done about all of this? One possibility is supplementation with the various identified compounds, not all of which can make it past the stomach without some form of protection. Some have been tested, with varying results. Another is fecal microbiota transplant, which has produced some quite eye-opening results on life span and measures of health in short-lived species such as killifish. As a treatment for severe conditions in which pathological microbes have taken hold in a patient's intestine, this approach to therapy has done quite well to date. It is not yet been assessed as a way to restore - even temporarily - a more youthful set of gut microbes in older people, as the animal evidence suggests it might.

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Age-related changes of the innate immune system are common and include shifts in the composition of immune cell populations, paralleled by the development of a chronic inflammatory state referred to as inflammaging. This is characterized by an imbalance between pro- and anti-inflammatory responses and fluctuations of inflammatory cytokines. The rate of inflammaging, quantified by measuring these markers, is strongly associated with age-related disability, disease, and mortality. It is theorized that inflammaging is driven by endogenous ligands released upon age-related tissue damage and can be aggravated by food excess and attenuated by caloric restriction, suggesting relevant cross-talk between metabolic and immune functioning.

Understanding how inflammaging is controlled could aid in the development of diagnostic and therapeutic tools for many age-related diseases associated with inflammation. Tryptophan (Trp) metabolism is associated with aging and produces metabolites that control inflammation, regulate energy homeostasis, and modulate behavior. The essential amino acid Trp fuels the synthesis of kynurenine (Kyn), serotonin (5-HT) and indoles. The Kyn pathway of Trp is the most active pathway of Trp metabolism and produces metabolites including kynurenic acid and nicotinamide adenine dinucleotide (NAD+). While indoleamine 2,3-dioxygenase (IDO) plays a minor role in Trp metabolism under normal circumstances, IDO-dependent Trp metabolism is strongly activated in response to interferons and other cytokines that are released upon inflammation. Inflammation-related IDO activity is often measured by the Kyn/Trp ratio in blood in diseases characterized by excessive or chronic inflammation including infections, autoimmune disorders, cardiovascular disease, and cancer.

Trp metabolism controls hyperinflammation and induces long term immune tolerance. These effects pivot on the ability of IDO to alter the local and systemic Kyn/Trp balance. This balance directly affects metabolic and immune signaling pathways that drive an anti-inflammatory response. The Kyn/Trp ratio, measured in blood, is robustly associated with aging in humans. The fact that this association is already evident in healthy young adults, and persists throughout life, implies that the age-dependent increase in the Kyn/Trp ratio is not secondary to the onset of disease but rather represents a physiological age-related change. Taken together, these observational data suggests that the Kyn/Trp ratio could provide a valuable marker for the rate of (physiological) inflammaging. As inflammaging is involved in the onset of age-related diseases, a marker for inflammaging should also predict the onset of age-related diseases. This is the case for the Kyn/Trp ratio.

Age-related changes to the microbiome were associated with increased expression of enzymes involved in microbial Trp metabolism. This highlights the importance of microbiota-dependent Trp metabolism and suggest that activation of intestinal IDO and age-related changes in microbiome composition can deplete the body of health-promoting indoles while affecting the systemic Kyn/Trp balance. In addition, it provides relevant evidence that links metabolic inflammation to gastrointestinal Trp metabolism and metabolic health.

More Aggressive Control of Blood Pressure Modestly Extends Life in Older People

Hypertension, the widespreak age-related increase in blood pressure, is very damaging. It is one of the major ways in which low-level biochemical damage, leading to stiffening of blood vessels and consequent disruption of the feedback mechanisms that determine blood pressure, gives rise to structural tissue damage throughout the body. Hypertension harms delicate tissues in the brain, kidneys, and elsewhere. Hypertension also speeds the development of atherosclerosis, the formation of fatty lesions in blood vessel walls, and makes it more likely that blood vessels weakened by plaques will rupture, leading to a heart attack or stroke. These and other mechanisms are why control of blood pressure, without controlling the underlying causes of hypertension, has a measurable effect on life expectancy.

Globally, an estimated 1.13 billion people have high blood pressure, or hypertension, which causes about 13% of all deaths, according to the World Health Organization. Almost 1,000 people in the U.S. die each day with high blood pressure as a primary or contributing cause, according to data from the Centers for Disease Control and Prevention. The research into hypertension care and life span found that with more intensive blood pressure control, focused on a target systolic blood pressure of less than 120 mmHg, a 50-year-old could expect to live almost three years longer. In order to achieve the lower blood pressure target, patients adopted healthy lifestyle habits and took blood pressure medications as prescribed.

At age 65, intensive treatment could extend life by more than a year, the research estimated. With intensive treatment, an 80-year-old would be expected to add almost 10 months to his or her life span. The new study builds on the 2015 findings of the landmark Systolic Blood Pressure Intervention Trial, or SPRINT, which tested the value of treating blood pressure intensively to reduce systolic readings to a lower target - below 120 mm Hg, instead of the routinely used target of below 140 mmHg. SPRINT, which followed patients for up to six years, found that the intensive approach reduced patients' risk of cardiovascular events by 25%. These events included heart attack, stroke, heart failure and cardiovascular-related death.

In this analysis, SPRINT data was evaluated to project the full life spans for patients treated intensively to meet the lower blood pressure target of 120 mmHg and for those who received standard care (systolic blood pressure target of less than 140 mmHg). Across age groups, intensive treatment for high blood pressure lengthened patients' remaining life span by 4% to 9%, compared with standard care, the study found.

Potentially Significant Gut Microbiome Changes Occur in Younger Adult Life

Researchers here provide evidence for detrimental changes in the composition of gut microbiota, and thus the compounds they secrete, to occur quite sharply at a threshold age as early as mid-30s. It is well known that the microbial populations of the gut change with age, and there are several identified mechanisms by which compounds secreted by beneficial gut microbes improve health over the long-term, or by which harmful gut microbes can spur chronic inflammation. It has been suggested that supplementation with some of these secreted compounds might be useful, or engineering of the microbial population to minimize harmful microbes and expand beneficial species.

Here, we have compared the proteins associated with the active fraction of the microbiota in infants, adults and elderly individuals. Ageing is associated with the progressive activation of gut bacteria, possibly because bacteria must react to increasing number of factors associated with preserving the health status in response to exposure to an increasing number of environmental conditions that are distinct and greater than the conditions experienced during early life stages. Most importantly, we identified a link between ageing and the microbial pathway associated with tryptophan and indole production and metabolism by the commensal microbiota. The key proteins involved in tryptophan-to-indole metabolism, TnaA and TrpB are both more abundant and expressed in the gut microbiota of infants. Both were expressed at significantly lower levels in adults and at even lower levels or below the detection limit in elderly individuals.

As shown in a recent study, indoles from commensal bacteria extend the healthspan of geriatric worms, flies and mice, and indoles may represent a class of therapeutics that improve the way we age, but not how long we live. The essential amino acid tryptophan, which is the least abundant in terms of its use in proteins, is provided by the diet or produced by gut bacteria, can cross the blood-brain barrier under the influence of the gut microbiota and is a biosynthetic precursor for a large number of complex microbial natural products. Recent in vitro studies have indicated the decreased production, transport, and catabolism of tryptophan in patients with a number of disorders.

Researchers have postulated that a chronological age threshold at which the composition of the microbiota suddenly changes does not exist, and changes occur gradually with time. However, compared with previous investigations, our study suggests a threshold or age at which the microbiota-based metabolism of tryptophan and indole begin to be significantly reduced, which may have health-related consequences on ageing if not treated accordingly. Indeed, based on our results, from the age of 11 years, the human gut microbiota may exhibit a decreased capacity to produce these metabolites, and from the age of 34 years, this capacity may be reduced by more than 90% compared to childhood. The results of this study reinforce the hypothesis that dietary supplementation with indole and tryptophan exert a beneficial effect on elderly individuals because their gut bacteria exhibit an impaired capacity to produce these molecules required for extending the healthspan. This supplement can be administered beginning at the age of 11 years, at which time a 50% decrease in the production of these metabolites occurs, and particularly beginning at the age of 34 years, when a greater than 90% reduction occurs

IL-15 as an Exercise Mimetic that Improves Wound Healing in Old Mice

Researchers here demonstrate that providing the cytokine IL-15 to older mice improves wound healing. The surrounding context suggests that this is a part of the stress response systems that link exercise to health benefits, acting through at least mitochondrial function, and no doubt other pathways as well. Since the mitochondria in cells throughout the body undergo a series of detrimental changes with age, faltering in their ability to deliver energy store molecules to power cellular processes, most methods of intervening in this decline might be expected to produce some degree of benefit. This is the case even when, as here, the intervention is essentially compensatory, addressing only a proximate cause rather than the underlying accumulation of damage that drives the manifestations of aging.

Impaired wound healing in elderly individuals increases infection risk and prolongs surgical recovery, but current treatment options are limited. Low doses of interleukin 15 (IL-15) that mimic exercise responses in the circulation improve skin structure and increase mitochondria in uninjured aged skin, suggesting that IL-15 is an essential mitochondrial signal for healing that is lost during aging.

Here we used gene microarray analysis of old and young murine epidermal stem cells and demonstrate that aging results in a gene signature characteristic of bioenergetic dysfunction. Intravenous IL-15 treatment rescued chronological aging-induced healing defects and restored youthful wound closure in old, sedentary mice. Additionally, exercise-mediated improvements in the healing of aged skin depend upon circulating IL-15. We show that IL-15 induces signal transducer and activator of transcription 3 (STAT3) signaling characteristic of young animals, reduces markers of growth arrest, and increases keratinocyte and fibroblast growth. Moreover, exercise or exercise-mimicking IL-15 treatment rescued the age-associated decrease in epidermal mitochondrial complex IV activity.

Overall, these results indicate that IL-15 or its analogs represent promising therapies for treating impaired wound healing in elderly patients.

Fibrosis as an Important Contributing Cause of Atrial Fibrillation

Researchers here argue that fibrosis of cardiac tissue is an important contribution to the development of atrial fibrillation in older patients. Fibrosis is a feature of many age-related conditions, a dysfunction in tissue maintenance processes that involves the generation of scar-like deposits of collagen by overactive fibroblasts. This scarring disrupts normal tissue structure and function in many organs, including the heart, and there is no good approved therapy to treat the progression of fibrosis: even slowing it is haphazard and unreliable.

This may soon change. Fibrosis appears to be caused to a large degree by the accumulation of lingering senescent cells. These errant cells are highly disruptive to tissue maintenance through inflammatory and other types of signaling. The development of senolytic therapies to selectively destroy senescent cells is well underway, and has been shown to reverse fibrosis in animal models. Some of the first human trials, using a combination of the generic drug dasatinib and supplement quercetin, are focused on fibrotic diseases such as idiopathic pulmonary fibrosis. Given continued success, this senolytic therapy should certainly be trialed as a means to treat fibrosis in other organs.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with high morbidity and mortality. It is well known that both the prevalence and incidence of AF increase sharply with age, particularly after 65 years of age. AF and aging share mutual bidirectional relationships. On the one hand, aging and aging-related underlying diseases result in myocardial remodeling that may lead to cardiac electrical abnormalities which enhance the occurrence or persistence of AF. On the other hand, AF worsens biological aging, specifically at the brain level, causing injuries related to ischemic and non-ischemic events, thereby impairing functional capacity. In addition, handling of AF is challenging in aged patients due to the high prevalence of complex clinical features (i.e. heart failure [HF] and chronic kidney disease) and the progressive AF-mediated aggravation of degenerative processes typical of aging. All these aspects have profound effects on the patient health condition and on the resources provided by the society and national health systems to dedicate to the care of elderly patients.

Even though it is well known that age is the single most important determinant of AF risk, the underlying mechanisms are not completely understood. Some of the mechanisms involved in the aging-AF association may be related with age-dependent left atrial dilation or senile amyloidosis that alter the structure of the myocardial tissue and constitute typical features of the so-called AF substrate. In addition, resting membrane potential depolarization and spontaneous calcium releases from the sarcoplasmic reticulum, among others, might promote afterdepolarization and trigger AF. Since fibrosis is a prominent lesion present in the atria of AF patients and atrial fibrosis can both affect the substrate and induce the trigger, this lesion emerges as a factor that may play a central role in aging-related AF. In particular, by increasing the severity of atrial fibrosis, age may contribute to the development of electrical conduction disturbances and ectopic activity, affecting atrial arrthythmogenity.

A Demonstration of Small Molecule Inhibition of Tau Aggregation

Researchers here demonstrate a small molecule approach to the inhibition of tau aggregation in neurodegenerative conditions. The tau protein is one of the few in the human body that can become altered in a way that leads to the aggregation of ever more molecules of the protein into solid deposits. These aggregates and their surrounding halo of harmful biochemistry cause cell dysfunction and cell death. Once the aggregation process starts, it spreads from cell to cell like an infection. This form of pathology is characteristic of a number of neurodegenerative conditions, designated as tauopathies, including later stages of Alzheimer's disease.

Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers.

In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain.

A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

Discovering New Mechanisms of Action for Metformin

Metformin is a terrible approach to slowing aging in comparison to, say, mTOR inhibition. Slowing aging in this way, by manipulating the operation of an aged cellular metabolism without repairing the underlying damage that causes aging, is in turn a terrible approach to the treatment of aging. Yet metformin attracts a great deal of interest. I believe that most people simply don't care about effect size and reliability. Most popular science materials don't discuss these points, thus putting every intervention on the same footing in the minds of much of the public. Yet effect size and reliability are the very heart of the matter.

The animal data on metformin shows it to be unreliable when it comes to effects on life span; results from different studies and different groups are quite varied. The one large human study to examine mortality and life span looked at people with type 2 diabetes, not healthy individuals. It is known that metformin disrupts the operation of mechanisms needed for benefits to health to arise from regular exercise - a significant issue. Lastly, even if taking the human data at face value, the effect size is really just not large enough to care about. Nothing in the research noted here changes any of this.

Previously, the only biochemical pathway that was known to be activated by metformin was the AMPK pathway, which researchers discovered stalls cell growth and changes metabolism when nutrients are scarce, as can occur in cancer. But the scientists believed more pathways than AMPK might be involved. The scientists developed a novel screening platform to examine kinases, the proteins that transfer phosphate groups, which are critical on/off switches in cells and can be rapidly flipped by metformin. Using this technology, the researchers were able to decode hundreds of regulatory "switch-flipping" events that could affect healthy aging.

The results revealed that metformin turns on unexpected kinases and pathways, many independent of AMPK. Two of the activated kinases are called Protein Kinase D and MAPKAPK2. These kinases are poorly understood, but are known to have some relation to cellular stress, which could connect them to the health-span- and life-span-extending effects observed in other studies. In fact, metformin is currently being tested in multiple large-scale clinical trials as a health-span- and life-span-extending drug, but the mechanism for how metformin could affect health and aging has not been clear. The current study indicates that Protein Kinase D and MAPKAPK2 may be two players in providing these therapeutic effects, and identifies new targets and cellular processes regulated by AMPK that may also be critical to metformin's beneficial effects.

"The results broaden our understanding of how metformin induces a mild stress that triggers sensors to restore metabolic balance, explaining some of the benefits previously reported such as extended healthy aging in model organisms taking metformin. The big questions now are what targets of metformin can benefit the health of all individuals, not just type 2 diabetics."

On Making Philanthropy in Support of Rejuvenation Research Attractive to Investors

In this interview, Aubrey de Grey of the SENS Research Foundation talks about how the foundation has sought to make philanthropy in support of the development of rejuvenation therapies an attractive prospect for high net worth investors, people who are usually much more interested in deploying capital into for-profit programs. Since the goal of the SENS community is to move projects from the lab to clinical development, particularly those promising projects in rejuvenation research that have previously lacked funding and moved more slowly than we'd all like, it should be quite compatible with the goals of investors. It makes sense to offer philanthropic support to programs that will later lead to startup biotech companies that are looking for investment.

How did Project 21 come into being?

The name Project 21 was always a bit of a misnomer. It wasn't really a project in any real sense, it was really just an umbrella name that we gave to our fundraising efforts, especially for high net worth donors. Basically, we had come to the conclusion that a very clear majority of the people who were giving us money or making positive noises about doing so tended to be investor types and were more inclined to give money to a benefactor than to charities. So the goal was to try to persuade people who were psychologically investors first and donors second to nevertheless support us. We felt that one thing that we had not emphasised sufficiently over the previous years, was the timeframe proximity of clinical trials - hence the focus on 2021.

How has Project 21 evolved since 2016?

Some of the more significant developments that have occurred are in terms of our business model. In 2016, we had barely started thinking in terms of spinning projects out as start-up companies. But it was in 2016 that Michael Greve came along - a German entrepreneur who made money in the early days of the web. He started giving us a million a year, but he also started investing a million a year in companies that were very much in our space, and was specifically interested in companies coming from our own projects. And that has worked out beautifully - he has now done that for a number of companies as well as a number of companies that are not spinouts from us, but are closely aligned with us.

And he's not been the only one, so now it's accurate to say that our business model is to work on important projects in this rejuvenation space for as long as it takes to get them to a point of sufficient proof of concept that an investor decides they can join the dots. As long as they can see the path from where we are to eventual revenue, and are therefore willing to back an actual for-profit entity. We've done this six or seven times now. But SENS Research Foundation is still a charity - we haven't shut up shop and declared victory yet. And that's because there are still some equally vital projects that have not reached an investable stage, so Project 21 is alive and kicking.

SENS Research Foundation is a charity - so how does the non-profit aspect connect with investors?

There is a big link. I always say to investors that if you're thinking about writing proper sized checks to start-up companies in the space, and you're happy with the really early stage of all of this - high risk, high reward - then you should also want to be donating to the foundation. What you will get for that is as much of my time as you want, which means that you will be in the position of having access to the information that will allow you to be a founding investor in the next start-up, which other people just won't have.

Back in 2015, we had one major donor, a very busy guy and seriously successful businessman, who, twice a year, would take an entire day to come visit us and get as much information as he was able to understand on everything we were doing. One day he turned around and said "Look, this project that you're funding - I think I can make money out of it." So he basically created a company, out of the blue, he took our people, gave us 10% of the company. And although that company was actually not successful, it changed our mindset completely. Since then, we have been aggressively pursuing that way of doing things, and all the other companies that we spun out have been very effective in terms of bringing in initial investment. It's definitely created a pipeline and I would say we are likely to be doing at least one a year, probably closer to two a year, for the foreseeable future.

The Latest on Cellular Senescence in Type 2 Diabetes

One of the more unexpected recent findings relating to cellular senescence is that it appears to be an important part of the mechanisms that lead to loss of the pancreatic β-cells responsible for insulin secretion in both type 1 diabetes and type 2 diabetes - which are very different conditions, despite the shared name. The authors of the brief open access commentary noted here discuss the present state of this research.

Age is one of the major risk factors for the development of type 2 diabetes mellitus (T2D). However, the understanding of how cellular aging contributes to diabetes pathogenesis is incomplete and as a result, current therapies do not target this aspect of the disease. In recent work we showed that insulin resistance induced the expression of aging markers, suggesting that β-cell aging could accelerate the progression toward diabetes. Therefore, reversing the hallmarks of cellular aging presents a potential avenue for novel T2D therapies; in particular, transcriptomic analysis of aged β-cells pointed us toward cellular senescence as a promising target.

Senescent cells enter a state of long-term growth inhibition and replicative arrest after exposure to environmental insults, including genomic damage, oncogene activation, and reactive oxygen species. The resulting changes in gene expression impair cell function and proliferation while modifying intercellular signaling through the senescence-associated secretory phenotype (SASP). The potential paracrine effects of senescent β-cells highlight the importance of the β-cell SASP in driving metabolic dysfunction.

Along these lines, we demonstrated that senescent β-cells downregulated hallmark identity genes, upregulated disallowed genes, and secreted proinflammatory cytokines. We established two models of insulin resistance in mice: one using the delivery of the insulin receptor antagonist S961, and the other using a more physiologically representative high fat diet. In both cases, the metabolic stress increased the number of senescent β-cells while impairing glucose tolerance. Aging and SASP genes were also upregulated, but after insulin resistance was stopped, gene expression returned to healthy levels. This suggests that there might be critical windows during which β-cell senescence may be reversible. These results were consistent with experiments on human β-cells, in which senescence increased with age, body mass index, and in the presence of T2D.

Additionally, we found that the targeted deletion of senescent cells, or senolysis, in mice improved β-cell function, reduced blood glucose levels, and restored healthy expression levels of aging and SASP genes. Our findings highlight the transformative therapeutic potential of senolytic drugs in restoring β-cell function among T2D patients. The partial reversibility of β-cell senescence suggests that, consistent with recent publications, this is a non-binary phenomenon. External insults may create subpopulations of aged β-cells activating distinct levels of the senescence-associated regulatory progression.

The progression of damaged β-cells through this regulatory cascade likely accelerates T2D; eventually, the accumulation of senescent β-cells may cross a threshold inducing long-term metabolic dysfunction through the permanent loss of β-cell mass and function. The deletion of senescent β-cells or the reversal of senescence in a targeted subpopulation of aged β-cells may inhibit this cascade of dysfunction. To advance these therapeutic strategies, it is imperative to characterize the distinct subpopulations of senescent β-cells and the temporal expression patterns of senescence genes.

Evidence for Exercise to Slow Cognitive Decline

A sizable body of evidence, both mechanistic and epidemiological, supports the idea that exercise slows age-related cognitive decline. The report here is an example of the type, noting the results of a study in which some of the participants were assigned to an exercise program. The exercising participants exhibited a slower decline in cognitive function, particularly memory, in comparison to the others. This is a representative result: in general, the consensus in the scientific literature is that regular exercise is beneficial to cognitive function over the long term.

Researchers theorized that the healthy lifestyle behaviors that slow the development of heart disease could reduce heart disease risk and also slow cognitive decline in older adults with cognitive impairment without dementia (CIND). These behaviors include regular exercise and a heart-healthy diet, such as the DASH (Dietary Approaches to Stop Hypertension) diet. Researchers designed a study titled Exercise and Nutritional Interventions for Cognitive and Cardiovascular Health Enhancement (or ENLIGHTEN for short). The goal of the study was to examine the effects of aerobic exercise and the DASH diet on cognitive functioning in older adults with CIND.

The ENLIGHTEN study examined 160 adults 55-years-old or older. The study participants were older adults who didn't exercise and had memory problems, difficulty thinking, and making decisions. They also had at least one additional risk factor for heart disease, such as high blood pressure (also known as hypertension), high cholesterol, diabetes, or other chronic conditions. Participants were randomly assigned to one of four groups: a group doing aerobic exercise alone, a group following the DASH diet alone, a group doing aerobic exercise and following the DASH diet combined, or a group receiving standard health education.

People in the exercise group did 35 minutes of moderate intensity aerobic exercise (including walking or stationary biking) three times per week for six months. They were supervised for three months and then exercised unsupervised at home for three months. Participants in the exercise group did not receive any counseling in the DASH diet and were encouraged to follow their usual diets for six months. The results of the research team's study showed that exercise improved the participants' ability to think, remember, and make decisions compared to non-exercisers, and that combining exercise with the DASH diet improved the ability to think, remember, and make decisions, compared to people who didn't exercise or follow the diet - even though they didn't perfectly follow the programs they were assigned to during the six-month interventions.

Reviewing the DNA Damage Response in Aging

Nuclear DNA damage is considered a contributing cause of aging, though at this stage the research community is still proposing and debating processes by which this damage might cause metabolic dysfunction throughout the body. Mutations to nuclear DNA evidently increase cancer risk, but setting this aside, how does random damage to random cells contribute to the declines of age?

There are a few possibilities; firstly that the vast majority of nuclear DNA damage, occurring as it does in somatic cells, or in unusued portions of the genome, is irrelevant. Harms are done when mutations affecting function occur in stem cells and progenitor cells, allowing that mutation to spread widely throughout a tissue. The second possibility, more recently proposed, is that all nuclear DNA damage systemically affects cell function wherever it occurs in the genome, because the processes of DNA repair have the side-effect of causing epigenetic changes characteristic of aging. Thirdly, higher levels of mutational damage may generate a greater burden of cellular senescence. Relative effect sizes of these processes are an open question, and much more work must be done to confirm that they are relevant in each case.

One important aspect of the ageing process is the accumulation of DNA damage through time. While containing the entire genetic information (except for mitochondria-encoded genes), the nuclear genome is constantly threatened by genotoxic insults, with an estimated frequency of the order of tens of thousands per day. These hazards can arise from exogenous or endogenous sources. Exogenous sources are, to some extent, avoidable; these include ultraviolet (UV) and ionizing radiation and a variety of genotoxic chemicals. Endogenous sources, on the other hand, are unavoidable as they include metabolic by-products, such as reactive oxygen species (ROS), and spontaneous chemical reactions that target DNA molecules (including alkylation and hydrolysis of DNA chemical bonds). The lesion type inflicted on the DNA greatly depends on the source of the damage. Lesions caused by endogenous sources tend to arise stochastically at a higher rate.

DNA damage can have distinctive consequences for cells. Persistent nucleotide substitutions, due to erroneous repair followed by misreplication, lead to the accumulation of permanent mutations and chromosomal aberrations, which increase the risk of cancer development. By contrast, bulky types of DNA lesions can block transcription and replication, triggering the arrest of the normal cell cycle, ultimately leading to cell senescence or cell death, both states preventing the cell from transforming into tumour cells but ultimately contributing to ageing. Nuclear DNA requires constant maintenance to be kept intact and error-free in order to avoid the aforementioned consequences. For this, cells evolved intricate, evolutionarily highly conserved machineries that mediate cellular responses to DNA damage-termed the DNA damage response (DDR). These highly complex systems include not only several repair pathways specific for different types of lesion but also distinct signalling cascades of damage sensors, signal boosters and effectors responsible for deciding the cell's fate.

This system has two immediate goals: (i) arrest the cell cycle to prevent the propagation of corrupted genetic information, while providing time to repair the damage, and (ii) actually coordinate the repair of the DNA lesion. Depending on the success of these previous steps, the cell's fate is then decided: after lesions are successfully repaired, the DDR signalling ceases, cells survive and return to their original state; however, impossible to repair lesions trigger a persistent DDR signalling which can then engender cellular senescence or apoptosis. Given the harmful consequences of irreparable DNA damage, it is not surprising that defects in DNA repair pathways are associated with severe human pathological conditions.

Research over past decades has elucidated the role of genomic instability as a root cause of ageing. The observed age-dependent accumulation of somatic mutations in the genome and the accelerated ageing phenotypes caused by deficiencies in DNA repair systems provide compelling evidence supporting an active role for intrinsic DNA damage in mediating loss of tissue functionality with ageing. Still, the broad range of phenotypic variability within ageing populations strongly suggests that complex signalling pathways might coordinate specific systemic responses to DNA damage. These systemic responses have become increasingly apparent in multiple species and appear to have a major role not only during the physiological ageing process but also in response to acute stress. Importantly, these responses represent perfect examples of the intricate connection between DNA damage and other hallmarks of ageing, such as cellular senescence, stem cell exhaustion, and altered intercellular communication, which can all occur as a consequence of the DDR. Nevertheless, the interplay between cell-autonomous and these non-cell-autonomous responses is still somewhat poorly understood.


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