Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Cytotoxic T Cells in the Aging Brain Contribute to Neurodegeneration
- The Gatekeepers of Medical Regulation are Horrified by Freedom, Responsibility, and Progress
- The Relationship Between the Gut Microbiome and Declining Immune Function in Aging
- Michael Greve Announces a New 300 Million Fund for Investment in Rejuvenation Biotechnology Startups
- Evidence Against the Membrane Pacemaker Hypothesis of Aging in Bird Species
- Inhibition of EN1 Activity Heals Skin Injuries without Scarring in Mice
- Advocating for the Reprogramming of Cells as a Path to Treat Aging
- Reviewing the Role of GDF11 in Aging
- The Interaction of Diet and Cellular Senescence in Aging
- ABL1 Inhibition Increases Neural Stem Cell Activity in the Aging Brain
- Selphagy Therapeutics Works on LAMP2A Upregulation to Promote Autophagy
- Changes in the Gut Microbiome Contribute to Hypertension, and are Diminished by Fasting
- Four Subtypes of Alzheimer's Disease Based on Differing Progression of Tau Pathology
- An Assessment of Various Lifestyle Interventions to Treat Sarcopenia
- Mesenchymal Stem Cell Therapy as a Treatment for Skin Aging
Cytotoxic T Cells in the Aging Brain Contribute to Neurodegeneration
The aging of the immune system causes a great deal of damage, and in many different ways. There are many varieties of immune cell in the innate and adaptive portions of the immune system, and pathological subsets are known to arise with age. Take age-associated B cells, for example, or the misconfigured T cells that contribute to varieties of autoimmune disorder, or the regulatory T cells that contribute to the pathology of heart failure, or the macrophages that become foam cells to accelerate atherosclerosis. There are many more examples.
To a first approximation, the immune system of the central nervous system is distinct from that of the rest of the body. The blood-brain barrier separates the two sides, allowing only some traffic to pass between. When looking closer, this is not entirely true, however. T-cells of the adaptive immune system can cross into the cerebrospinal fluid in small numbers, particularly in disease states, and there is evidently some mode of communication between the immune systems of the central nervous system and the rest of the body, given that they both respond to threats that occur on only one side of the blood-brain barrier.
Researchers here present evidence for aggressive, cell-killing T cells to make their way to the brain in increasing numbers with age, and there cause problems that contribute to neurodegeneration and cognitive decline. Whether this is an extension of the existing and better regulated traffic that takes place in youth, or the consequence of blood-brain barrier dysfunction, or some other collection of mechanisms to allow passage, remains an open question.
Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline
Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon-myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages - important representatives of the innate immune system - are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses.
Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes.
Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function.
The Gatekeepers of Medical Regulation are Horrified by Freedom, Responsibility, and Progress
Much pearl-clutching is in evidence in a recent article on the existence of groups, such as Libella Gene Therapeutics, attempting to prototype telomerase gene therapies via patient paid trials, or such as Integrated Health Systems and BioViva, trying to develop markets for such therapies via medical tourism. The gatekeepers of medical regulation stand in opposition to the idea that patients and their supporters can make responsible decisions about risk, based on the available data. Medicine is somehow a privileged space, different from every other human endeavor, in which only the anointed priesthood are allowed to determine what is and is not allowed. It is reprehensible. Analysis has shown that this attitude, and the system of regulation that accompanies it, costs a great many lives by slowing the development of new therapies and limiting the opportunities for treatment.
Medicine, like every form of service, works best in an environment of review organizations, competition, and due diligence by customers. At the end of the day, it is always a matter of caveat emptor. And this already happens, as anyone who has been through a scheduled surgery can tell you. Patients absolutely shop the market to the degree that present regulation allows them to do so, and there is a robust system of legal culpability by which fraud and harm can be prosecuted. As is the case in every other industry, providers of medical services have financial and other incentives to produce good results for patients.
I personally do not have a strong opinion on whether the telomerase gene therapy that is the subject of this article will help with Alzheimer's disease; it seems indirect and compensatory, improving cell function rather than striking directly at the known causes. That said, several noted research groups are very much in favor of developing telomerase based therapies for human use, and at least one company in the longevity industry, Telocyte, is seeking to raise funding to run a formal trial of telomerase gene therapy for Alzheimer's disease within the existing regulatory system. It is an entirely mainstream goal.
At some point all new medical technologies must be tried for the first time in humans. Is that to be left to the anointed priesthood, with its impossible goal of zero patient risk, ever increasing costs of certification, and ever fewer approvals with each passing year? Or should we live in a more reasonable world in which more sensible and cost-effective choices regarding risk, pace of development, and availability of treatments are made by patients, supporters, and networks of review organizations, rather than by uncaring bureaucrats? I would vote for the latter of these two options.
Six patients with dementia went to Mexico for an unproven gene therapy, a biotech CEO claims
Six patients with dementia traveled to Mexico last year to be injected with a gene therapy not authorized for use in the U.S., according to the CEO of a Seattle-area startup that wants to accelerate testing of unproven anti-aging medicines and views U.S. drug safety regulations as a hindrance. At the heart of the project is a controversial biotech called BioViva, whose CEO had herself injected with an experimental gene therapy in Colombia and whose advisory board includes renowned Harvard geneticist George Church. It is part of a growing ecosystem of entrepreneurs and scientists, dreamers and schemers, who believe aging is not inevitable and aim to develop treatments to extend the human life span.
Last month, during a talk hosted by the National University of Singapore, the CEO, Elizabeth Parrish, divulged that she was eagerly awaiting data from a human study involving six patients who received an experimental gene therapy. On Friday, she told STAT the procedures were done last year in Mexico. If true, it would be the first known attempt to use the technique to treat age-related dementia, which is most often caused by Alzheimer's disease.
STAT set out to independently verify the accuracy of Parrish's claims. While many key details could not be confirmed, including the identities of these six patients and how the purported treatment affected them, STAT found evidence that BioViva and partners were recruiting patients. A newsletter emailed by BioViva in 2019 said 10 patients over age 50 with mild to moderate Alzheimer's were needed for a study of a gene therapy. The one-hour procedure, according to an FAQ linked from the email, would be done in Mexico City and involved a one-time injection. The effort raises the specter of an overseas medical tourism industry targeting patients desperate to lengthen their lives and offering unproven treatments that would permanently alter the genetic code inside recipients' cells.
The Relationship Between the Gut Microbiome and Declining Immune Function in Aging
The composition of the gut microbiome changes with age, becoming less helpful and more inflammatory as the proportion of actively harmful bacteria grows. There are many contributing causes with plausible supporting evidence in the scientific literature, including dietary changes characteristic of late life, immune aging, intestinal tissue dysfunction that is downstream of stem cell aging or senescent cell accumulation, and so forth. As is often the case in these matters, it remains unclear as to which of these causes are the most relevant targets for the development of therapies.
That said, it is possible to produce some reversal of aspects of microbiome aging in mice by innoculation with flagellin. This spurs the immune system to more aggressively destroy problematic gut microbes that manufacture flagellae in order to move into gut tissue. That this intervention is beneficial to a meaningful degree suggests that immune aging is an important cause of harmful shifts in gut microbiome populations. In fact, one can argue for a bidirectional relationship, in which the immune system falters in its gardening of the microbiome with advancing age, but a part of that faltering is caused by the activities of inflammatory microbes.
The aging gut microbiome and its impact on host immunity
The microbiome plays a fundamental role in the maturation, function, and regulation of the host immune system from birth to old age. In return, the immune system has co-evolved a mutualistic relationship with trillions of beneficial microbes residing our bodies while mounting efficient responses to fight invading pathogens. As we age, both the immune system and the gut microbiome undergo significant changes in composition and function that correlate with increased susceptibility to infectious diseases and reduced vaccination responses. Emerging studies suggest that targeting age-related dysbiosis can improve health- and lifespan, in part through reducing systemic low-grade inflammation and immunosenescence - two hallmarks of the aging process. However, a cause and effect relationship of age-related dysbiosis and associated functional declines in immune cell functioning have yet to be demonstrated in clinical settings.
Given the ever-growing impact of the gut microbiome on the host immune system, it is reasonable to speculate that restoring age-related declines in gut microbial richness and function - be it through personalized nutrition or supplements - may represent a prophylactic measure to fight functional declines in immune fitness. In this context, prebiotics, probiotics, and postbiotics or synbiotics with the ability to reinforce immunity through supporting intestinal barrier integrity or by regulating inflammatory processes have been tested in clinical settings. However, a lack of consistency between studies, strain specific differences or doses, prebiotic nature and quantity, or age and medical conditions of the subjects have made it difficult to validate the effectiveness of such approaches to reinforce age-associated declines in host-immune fitness.
None the less, mining the gut microbiome is a treasure trove waiting to be unlocked, and gerontology is no exception here. As exemplified by numerous preclinical studies, restoration of a youthful microbiome has rejuvenating potential for the aged host through sustaining immunity and health-span. Thus, a better understanding of the dynamic age-related changes in gut microbial community structures and associated metabolome, how such alterations affect cellular immune networks and how these pathways can be therapeutically targeted will have wide-reaching implications for future strategies to reinforce or even rejuvenate the aging immune system.
Michael Greve Announces a New 300 Million Fund for Investment in Rejuvenation Biotechnology Startups
Michael Greve, you might recall, is a strong supporter of the Strategies for Engineered Negligible Senescence (SENS) rejuvenation biotechnology approach to aging, first put forward twenty years ago by Aubrey de Grey and collaborators. Five years ago Michael Greve pledged 10 million to be split between SENS-focused research and investment in startup companies arising from that research. His venture firm, Kizoo Technology Ventures, has invested in companies that are developing potential rejuvenation therapies, such as the cross-link breaking enzymes of Revel Pharmaceuticals, and the senolytic suicide gene therapy of Oisin Biotechnologies. He founded a non-profit, Forever Healthy Foundation, that, among other things, runs the Undoing Aging conference series and publishes serious, sober, detailed technical reviews of approaches to treating aging. Now Michael Greve is greatly expanding his efforts to support the new and growing longevity industry.
In the SENS viewpoint, which is itself a synthesis of evidence gathered over past decades of scientific research, aging is caused by the accumulation of fundamental forms of well-known cell and tissue damage that arise as a side-effect of the normal operation of metabolism. The best approach to intervention is to periodically repair that damage. Repair is explicitly rejuvenation.
Scientists and supporters of SENS advocated for removal of the senescent cells that accumulate in old tissues a decade before the rest of the scientific community came around to supporting that idea. The animal data produced since then shows that clearance of senescent cells produces profound reversals of aging and age-related disease in old mice. It is even capable of reversing the detrimental restructuring of the heart in old individuals that leads to heart failure. Now, a good fraction of the growing longevity industry is pursuing the development of senolytic therapies capable of selective destruction of senescent cells. Thus to my eyes, the more support there is for the SENS approach to the challenge of aging the better. It is clearly the right way forward towards meaningful control over aging within our lifetimes.
Kizoo commits 300 million to advance rejuvenation startups
Michael Greve, founder of the Forever Healthy Foundation and owner of Kizoo Technology Ventures, announced today that he will make available an additional 300 million to be invested in rejuvenation biotech. The funds, to be deployed via Kizoo, will be used to create and support more startups in the rejuvenation space. They will also allow Kizoo to maintain a strong commitment to its key startups during follow-up rounds and to advance the therapies from clinical development to public availability.
With this 300 million commitment, Greve and Kizoo double down on their mission to accelerate the advent of rejuvenation biotechnology by doing lighthouse investments in entirely new, repair-based approaches that treat the root causes of aging and thus overcome age-related diseases. Through the creation of successful companies, they seek to inspire scientists, investors, and the general public by demonstrating that human rejuvenation is not science fiction anymore and that the resulting therapies are affordable and uncomplicated.
Technologies pioneered by Kizoo's startups include removal of arterial plaque, decalcification of aged tissue, breaking of protein-glucose cross-links, and delivery of new mitochondria to aged cells - all aiming to prevent and repair common age-related conditions such as myocardial infarction, stroke, high blood pressure, tissue stiffening, skin aging, and loss of muscle function.
"I am really grateful that we can use the funds we have created with our highly successful technology ventures to contribute to the quest to get aging under full medical control and to make age-related diseases a thing of the past. For me, it is a worthy cause that is exciting in a technological, commercial, and above all, a humanitarian way." Greve expects that the new funds, in combination with the strong, multi-round commitment of Kizoo to its key startups, should trigger co-investments of up to 3-4 times the initial amount, resulting in a significant acceleration of the development and public availability of the therapies.
Evidence Against the Membrane Pacemaker Hypothesis of Aging in Bird Species
The membrane pacemaker hypothesis suggests that the lipid composition of membranes, and particularly mitochondrial membranes, is an important determinant of species longevity in at least some clades, such as mammals and birds. Membrane composition determines the degree of resistance to lipid oxidation and consequent loss of function for component parts of a cell. Aging is associated with a rise in oxidative stress placed upon cells and their structures, related to chronic inflammation and mitochondrial dysfunction.
Over the years, a fair amount of supporting evidence has been gathered for this view of species longevity, but the paper here stands in opposition to that work, at least for bird species. It is worth noting that birds, and other flying species, are metabolically quite different from near relative non-flying species. The high metabolic demands of flight lead to adaptations that clearly impact aging in many cases, such as for some bat species with noted longevity, perhaps largely through mitochondrial function, perhaps not. That said, the membrane pacemaker hypothesis was thought to be relevant in both mammals and birds. As usual, all too little is simple, straightforward, and a settled matter when it comes to the details of cellular metabolism and aging.
No Evidence for Trade-Offs Between Lifespan, Fecundity, and Basal Metabolic Rate Mediated by Liver Fatty Acid Composition in Birds
The fatty acid composition of biological membranes has been hypothesised to be a key molecular adaptation associated with the evolution of metabolic rates, ageing, and life span - the basis of the membrane pacemaker hypothesis (MPH). MPH proposes that highly unsaturated membranes enhance cellular metabolic processes while being more prone to oxidative damage, thereby increasing the rates of metabolism and ageing. MPH could, therefore, provide a mechanistic explanation for trade-offs between longevity, fecundity, and metabolic rates, predicting that short-lived species with fast metabolic rates and higher fecundity would have greater levels of membrane unsaturation.
However, previous comparative studies testing MPH provide mixed evidence regarding the direction of covariation between fatty acid unsaturation and life span or metabolic rate. Moreover, some empirical studies suggest that an n-3/n-6 PUFA ratio or the fatty acid chain length, rather than the overall unsaturation, could be the key traits coevolving with life span. In this study, we tested the coevolution of liver fatty acid composition with maximum life span, annual fecundity, and basal metabolic rate (BMR), using a recently published data set comprising liver fatty acid composition of 106 avian species.
While statistically controlling for the confounding effects of body mass and phylogeny, we found no support for long life span evolving with low fatty acid unsaturation and only very weak support for fatty acid unsaturation acting as a pacemaker of BMR. Moreover, our analysis provided no evidence for the previously reported links between life span and n-3 PUFA/total PUFA or MUFA proportion.
Our results rather suggest that long life span evolves with long-chain fatty acids irrespective of their degree of unsaturation as life span was positively associated with at least one long-chain fatty acid of each type (i.e., SFA, MUFA, n-6 PUFA, and n-3 PUFA). Importantly, maximum life span, annual fecundity, and BMR were associated with different fatty acids or fatty acid indices, indicating that longevity, fecundity, and BMR coevolve with different aspects of fatty acid composition. Therefore, in addition to posing significant challenges to MPH, our results imply that fatty acid composition does not pose an evolutionary constraint underpinning life-history trade-offs at the molecular level.
Inhibition of EN1 Activity Heals Skin Injuries without Scarring in Mice
There is an interesting history of accidental discoveries when it comes to exceptional regeneration in mammals, such as the MRL mice that are capable of regenerating the ear tags and notches that researchers use to track mice through experiments, thereby causing some confusion. Researchers have since then spent time on attempts to identify important mechanisms by which mammalian regeneration takes the path of scarring, rather than the path of regrowth. The discovery noted here is an interesting one. The scientists involved have established a good proof of concept based on a regulator of scarring, EN1. When suppressed this leads to the complete regeneration of skin injuries without scar formation.
Skin wounds generally heal by scarring, a fibrotic process mediated by the Engrailed-1 (En1) fibroblast lineage. Scars differ from normal unwounded skin in three ways: (i) They lack hair follicles, sebaceous glands, and other dermal appendages; (ii) they contain dense, parallel extracellular matrix fibers rather than the "basket-weave" pattern of uninjured skin; and (iii) as a result of this altered matrix structure, they lack skin's normal flexibility and strength. A successful scar therapy would address these three differences by promoting regrowth of dermal appendages, reestablishment of normal matrix ultrastructure, and restoration of mechanical robustness. However, little is known about the cellular and molecular mechanisms blocking a regenerative healing response in postnatal skin, or whether these mechanisms can be bypassed by modulating specific fibroblast lineages.
We asked whether scarring fibroblasts are derived purely from expansion of existing En1 lineage-positive fibroblasts present in unwounded skin, or whether En1 scar fibroblasts could arise de novo by activation of En1 expression in postnatal, En1 lineage-negative fibroblasts within the wound niche. We used fibroblast transplantation as well as transgenic mouse models to trace En1 expression in a spatiotemporally defined fashion. Next, we studied fibroblast responses to mechanical forces in vitro and in vivo to establish a mechanotransduction mechanism linking skin tension to postnatal En1 expression. Finally, we used chemical (verteporfin) and transgenic inhibition of mechanotransduction signaling to modulate En1 expression during wound healing.
Fibroblast transplantation and lineage-tracing studies reveal that En1 lineage-negative fibroblasts (ENFs) of the reticular (deep) dermis activate En1 in the wound environment, generating ~40 to 50% of scar fibroblasts. This phenomenon depends on mechanical cues. Comparison of ENFs with En1-expressing and En1 knockdown fibroblasts by RNA sequencing suggests that En1 regulates a wide array of genes related to skin fibrosis. In healing wounds, YAP inhibition by verteporfin blocks En1 activation and promotes ENF-mediated repair, yielding skin regeneration in 30 days with recovery of functional hair follicles and sebaceous glands. This suggests that modulation of En1 activation, whether direct or indirect, can yield wound regeneration.
Advocating for the Reprogramming of Cells as a Path to Treat Aging
A fair number of researchers consider cellular reprogramming to be a promising path forward for the treatment of aging. Some of these think that epigenetic change is an important cause of of aging, while others see the epigenetic changes characteristic of aging as a downstream consequence of underlying processes of damage, but consider reprogramming to be a potentially useful point of intervention regardless. Reprogramming as a basis for therapy entails at least partially pushing cells towards pluripotency, in the same manner as the production of induced pluripotent stem cells, but not so far down this path that they lose their differentiated identity as well as ability to function. As a side-effect, the epigenetic patterns of gene expression are reset to a more youthful configuration. Mitochondrial function improves, cell function improves. This cannot repair DNA damage, and will likely also struggle with some of the other issues of aging, such as the accumulation of waste products in long-lived cells. It does, however, appear to produce benefits in animal models, in early exploratory studies.
Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal somatic cells, which age and die. In this review, we describe the germline as clock-free and somatic cells as clock-bound and discuss aging with respect to three DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks.
The initiation of the DNA methylation aging clock, the telomeric clock, and perhaps other clocks at the beginning of development suggests an intimate relationship between development and aging. Indeed, the adaptation of developmental clock rate to environmental pressure could account for the wide variation in lifespan observed between species. For example, humans and naked mole-rats exhibit neoteny, where slowing the rate of development correlates with an extension of lifespan. The application of germline strategies in somatic stem cells has resulted in the remarkable regenerative capacity of lower life forms that are capable of indefinite lifespans, such as sponges, planarians, and hydra. This regenerative capacity has become increasingly restricted as more complex life forms evolved, being confined prior to the embryonic to fetal transition period in mammals. However, retention of extensive capacity for regeneration is observed in lower vertebrates, including fishes, amphibians, and reptiles, which also exhibit remarkable phenotypic plasticity in their capacity for metamorphosis and in certain cases of remarkable reversals of developmental stage and sexual development.
Finally, reprogramming using germline factors can uncover a similar but latent phenotypic plasticity in mammals by reverting both the developmental state and cellular age. Indeed, both natural phenotypic plasticity in the blue wrasse and partial reprogramming involve the repression of DNA methyl transferases and induction of demethylases which, by a yet-to-be-determined mechanism, may enable the DNA methylation clock to tick backward. The discovery that partial reprogramming can reverse the aging clock without permanent alteration of cellular identity has led to initial studies that demonstrate the potential to reverse organismic aging. Although there are many challenges ahead, our current understanding of cellular clocks and our ability to reprogram them using germline factors opens the door to many promising therapeutic approaches to slowing down, preventing, or reversing aging itself and thus treating the many age-related diseases that burden society. Indeed, if these approaches can be made practical and scalable, we may find ourselves in a future in which we have no time to age.
Reviewing the Role of GDF11 in Aging
In heterochronic parabiosis, the circulatory systems of an old and young animal are connected. The young animal exhibits some aspects of accelerated aging, while the old animal exhibits some degree of rejuvenation. Early investigations focused on the supply of factors in young blood to the old animal as the causative mechanism, and GDF11 was one of the first such factors identified for further research and development. There has been some controversy over the published works on this topic, however, stemming initially from technical issues involved in working with GDF11, then later from investigations that point to dilution of harmful factors in old blood being the dominant mechanism in heterochronic parabiosis. The company Elevian claims to have resolved these issues, and is advancing therapies based on delivering GDF11, but it will probably be at least a few more years before there is a clear view into the details of their work.
Growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, has recently received attention because of its numerous functions in modulating the development and differentiation of various tissues and organs. Studies regarding the role of GDF11 in the development of various diseases have been conducted in recent decades. GDF11 is reportedly beneficial with respect to controlling age-related cardiac hypertrophy, improving muscle tone, preventing degeneration in the central nervous system, enhancing cognitive function, and promoting tissue regeneration.
Important parabiosis experiments involving two animals of different ages, performed in 2013 and 2014, revealed that GDF11 levels were disrupted in an age-related manner in vascular, neurogenic, and skeletal muscle tissues. Those findings suggested that GDF11 may be regarded as an honorable "rejuvenation" factor that could restore regenerative function, thus resisting aging and extending longevity. A study in fish revealed that GDF11 has rejuvenation capacity to extend the lifespan. In 2020, a plasma proteomic dataset demonstrated that the GDF11 protein can significantly extend the lifespan.
These studies demonstrated critical roles for GDF11 in the inhibition of aging. However, recent studies have yielded conflicting data regarding the ability of GDF11 to alleviate dysfunction in age-related diseases. Thus, the regeneration ability of GDF11 with respect to age-related dysfunction requires further investigation. This review provides an overview of GDF11 and its functions in age-related diseases. It also discusses potential underlying mechanisms for the effects of GDF11 in age-related diseases.
The Interaction of Diet and Cellular Senescence in Aging
The authors here tout a discussion of diet and cellular senescence, but in fact deliver a discussion on obesity, calorie restriction, and cellular senescence. One of the mechanisms by which excess visceral fat tissue causes chronic inflammation and pathology is by increasing the pace at which senescent cells are produced. The number of lingering senescent cells increases with age, and these cells disrupt the function of the immune system and surrounding tissue via their inflammatory secretions. Calorie restriction, on the other hand, upregulates stress response mechanisms that can slow the pace at which senescent cells are created. It also preserves the function of the immune system into later life, thereby increasing the pace at which they are destroyed by the immune system at any given age.
Normal human cells do not divide indefinitely. When cultured in vitro, cells can undergo only a finite number of divisions before entering in a nondividing state, the so-called replicative senescence. Senescence has been suggested both as contribute and a consequence of the ageing process and is involved in the development of many age-related chronic diseases. Cellular senescence is a state of an irreversible growth arrest that occurs in response to various forms of cellular stress and is characterized by a pro-inflammatory secretory phenotype.
Multiple studies showed that cellular senescence occurs in both physiological and pathophysiological conditions. Senescent cells accumulate with ageing and can contribute to age-related decline in tissue function. Obesity is a metabolic condition that can accelerate the ageing process by promoting a premature induction of the senescent state of the cells. In contrast, caloric restriction without malnutrition is currently the most effective non-genetic intervention to delay ageing, and its potential in decreasing the cellular senescent burden is suggested.
The precise mechanisms underlying the effect of obesity in the induction of premature cellular senescence are poorly understood and warrant further investigation. Moreover, more studies are required to understand how lowering calories intake reduces cellular senescence burden, and whether this can directly lower levels of molecules involved in the inflammation process, like interleukins, which, for instance, could also be promoted by other variables independently altered by senescence. Plus, in obesity and ageing studies, the researchers tend to focus on one specific organ or pathology type, which limits the information that may be collected about the temporal biological order of senescence induction. Thus, more in vitro studies are required especially in cellular model systems that can replicate the alterations seen during in vivo progression in the ageing process.
ABL1 Inhibition Increases Neural Stem Cell Activity in the Aging Brain
Putting stem cells back to work is the theme of a great of the research that takes place in the regenerative medicine community. Stem cells are responsible for producing a supply of daughter somatic cells, required to replace losses and maintain functional tissue. Stem cell activity throughout the body declines with age, however. Much of this decline is not caused by intrinsic cell and tissue damage that would prevent activity, but is rather an evolved reaction to the presence of that damage.
Suppressing stem cell activity likely serves to reduce cancer risk in later life. The more cell activity there is in a damaged environment, the greater the odds that cancerous cells will arise. Unfortunately, the consequence of a reduced rate of rapid death by cancer is the certainty of a slow and drawn out decline due to organ failure. Thus, there are projects such as the one noted here, in which scientists search for ways to force stem cells into greater activity, despite the presence of damage.
By tracing individual neural stem cells (NSCs) in mice over the course of several months, researchers identified "short-term NSCs" that quickly differentiate into more specialized neurons, and "long-term NSCs" that continually divide and replicate themselves to maintain an ongoing reserve of stem cells with the ability to generate many different cell types in the brain. This key population of long-term NSCs divided less often and failed to maintain their numbers as the mice aged.
The scientists next examined thousands of genes in the long-term NSCs, which were dividing less often and had slipped into an inactive state known as quiescence. The gene activity of the quiescent NSCs varied greatly in young versus middle-aged animals. As expected, there were changes in genes that control how long-term NSCs divide, as well as generate new neurons and other brain cells. Remarkably, there were many important changes in gene activity related to biological aging at younger ages than anticipated. These pro-aging genes make it more difficult for cells to repair damage to their DNA, regulate their genetic activity, control inflammation, and handle other stresses. Among the pro-aging genes, the scientists were most intrigued by Abl1, which formed the hub of a network of interrelated genes.
Using an existing, FDA-approved chemotherapy drug called Imatinib, scientists could easily inhibit the activity of the gene Abl1. The scientists gave older mice doses of Imatinib for six days. After the drug blocked the activity of the gene Abl1, the NSCs began to divide more and proliferate in the hippocampus, the part of the brain responsible for learning and memory. We've succeeded in getting neural stem cells to divide more without depleting, and that's step one. Step two will be to induce these stem cells to make more neurons. Step three will be to demonstrate that these additional neurons actually improve learning and memory."
Selphagy Therapeutics Works on LAMP2A Upregulation to Promote Autophagy
It has been more than a decade since researchers demonstrated that genetic engineering of mice to boost LAMP2A levels in the liver produced a sizable rejuvenation of liver function in old animals. This happens because increased levels of LAMP2A cause an upregulation of chaperone-mediated autophagy, a cellular maintenance process responsible for removing damaged molecules and structures in the cell. This makes cells more functional, and thus the tissue more functional. Since then, work on LAMP2A and autophagy has continued. Nowadays, the same research group that produced the liver results is a part of Selphagy Therapeutics within Life Biosciences, developing a small molecule approach to LAMP2A upregulation. This will inevitably be far less effective than gene therapy, but small molecules are still the way that most research programs move to the clinic, a function of the very conservative nature of venture funding and regulation in the biotech space.
All cells maintain a network of cleaning systems that remove and recycle unwanted proteins. One school of thought holds that when the process, called autophagy, malfunctions in neurons, the toxic buildup of proteins can promote neurodegenerative diseases such as Alzheimer's. Now, scientists have shown that a drug designed to invigorate a specialized cellular garbage disposal mechanism ameliorated symptoms in two mouse models of Alzheimer's.
The system the drug targets is called chaperone-mediated autophagy (CMA), in which single proteins are selected and escorted to spherical vesicles in cells called lysosomes, where they are then degraded. Once at the lysosome, the protein-chaperone complex binds to receptors called lysosome-associated membrane protein type 2A (LAMP2A) to trigger the destruction process. The drug, called CA, works by ramping up LAMP2A to boost CMA activity.
CMA activity normally drops as people age, but neurodegenerative disease can make it worse, further affecting the normal protein balance in the brain. The researchers tested whether a CMA activator like CA could protect against Alzheimer's. They gave the oral drug to mice that either had a tau abnormality or a combination of toxic tau and beta-amyloid protein clumps. The drug significantly reduced levels of tau and beta-amyloid, as well as plaques, in the brains of the animals. The treatment also normalized the animals' walking ability and improved visual memory, anxiety- and depression-like behaviors, and neuromuscular strength.
Changes in the Gut Microbiome Contribute to Hypertension, and are Diminished by Fasting
Researchers here provide evidence for alterations in the gut microbiome to be an important contributing case of raised blood pressure, or hypertension. Fasting reduces blood pressure, and here it is demonstrated that this is due in part to improvements in the state of the microbial populations of the gut. It is well known that the gut microbiome changes with age, losing beneficial populations and gaining harmful populations. This study suggests that some of those changes contribute to age-related hypertension, providing yet another reason to put resources into the near term development of therapies that can reverse the aging of the gut microbiome, such as flagellin vaccination or fecal microbiota transplantation.
"Previous studies from our lab have shown that the composition of the gut microbiota in animal models of hypertension, such as the SHRSP (spontaneously hypertensive stroke-prone) rat model, is different from that in animals with normal blood pressure. Further, transplanting dysbiotic gut microbiota from a hypertensive animal into a normotensive one results in the recipient developing high blood pressure. This result told us that gut dysbiosis is not just a consequence of hypertension, but is actually involved in causing it. This ground work led to the current study in which we proposed to answer two questions. First, can we manipulate the dysbiotic microbiota to either prevent or relieve hypertension? Second, how are the gut microbes influencing the animal's blood pressure?"
Researchers drew on previous research showing that fasting was both one of the major drivers of the composition of the gut microbiota and a promoter of beneficial cardiovascular effects. Working with the SHRSP model of spontaneous hypertension and normal rats, the researchers set up two groups. One group had SHRSP and normal rats that were fed every other day, while the control group had SHRSP and normal rats with unrestricted food availability. Nine weeks after the experiment began, the researchers observed that, as expected, the rats in the SHRSP control had higher blood pressure than the normal control rats. Interestingly, in the group that fasted every other day, the SHRSP rats had significantly reduced blood pressure when compared with the SHRSP rats that had not fasted.
The researchers transplanted the microbiota of the rats that had either fasted or fed without restrictions into germ-free rats, which have no microbiota of their own. The germ-free rats that received the microbiota of normally fed SHRSP rats had higher blood pressure than the germ-free rats receiving microbiota from normal control rats, just like their corresponding microbiota donors. Additionally, germ-free rats that received microbiota from the fasting SHRSP rats had significantly lower blood pressure than the rats that had received microbiota from SHRSP control rats.
Four Subtypes of Alzheimer's Disease Based on Differing Progression of Tau Pathology
Researchers have recently proposed a taxonomy of subtypes of Alzheimer's disease based on differences in the spread of tau protein aggregation through the brain that is characteristic of the later stages of the condition. Tau aggregation caused dysfunction and cell death in neurons. It is interesting to speculate as to the underlying reasons why there are four such classes of progression of tau pathology. Why only four? Why so clearly four? One might suggest - with absolutely no evidence to hand as of yet - that this has something to do with differing rates of age-related failure among the few drainage pathways by which cerebrospinal fluid leaves the brain, for example. This drainage allows the removal of molecular waste from the brain, its loss is implicated in Alzheimer's disease, and it is possible that drainage rates falter more or less rapidly in different parts of the brain for different people.
Alzheimer's disease is characterized by the abnormal accumulation and spread of the tau protein in the brain. An international study can now show how tau spreads according to four distinct patterns that lead to different symptoms with different prognoses of the affected individuals. "In contrast to how we have so far interpreted the spread of tau in the brain, these findings indicate that tau pathology in the brain varies according to at least four distinct patterns. This would suggest that Alzheimer's is an even more heterogeneous disease than previously thought. We now have reason to reevaluate the concept of typical Alzheimer's, and in the long run also the methods we use to assess the progression of the disease."
Researchers used a study population of 1,143 individuals who were either cognitively normal or individuals who had developed Alzheimer's in various stages. An algorithm was applied to the data from the tau PET images from the 1,143 individuals, the so-called SuStaIn (Subtype and Staging Inference) algorithm. As expected, many individuals did not show any abnormal tau PET signal, and these were therefore automatically assigned to a tau-negative group. By then cross-validating the tau PET images with a sixth independent cohort, and following up the individuals for about two years, the researchers were able to develop four patterns that best represented the data from the remaining individuals.
"We identified four clear patterns of tau pathology that became distinct over time. The prevalence of the subgroups varied between 18 and 30 percent, which means that all these variants of Alzheimer's are actually quite common and no single one dominates as we previously thought."
An Assessment of Various Lifestyle Interventions to Treat Sarcopenia
A sizable fraction of sarcopenia, the loss of muscle mass and strength with age, is avoidable. Not all of it, of course, at least not without advances in therapies targeting the underlying mechanisms of aging. But it is in part the consequence of a lack of physical activity, with other contributions arising from diet, changes to the gut microbiome, and chronic inflammation. There is extensive data on the ability of structured exercise programs, such as strength training, to reverse measures of sarcopenia in older individuals. A more comprehensive set of lifestyle changes is assessed in this study, with varying outcomes. Physical activity still appears to come out ahead.
Few studies have comprehensively described changes in blood biomarkers of the physiological responses that underlie the sarcopenia reduction that is associated with lifestyle interventions. In this study, we performed secondary analyses of data in a randomized controlled trial of multi-domain lifestyle interventions (6-month duration physical exercise, nutritional enrichment, cognitive training, combination and standard care control) among 246 community-dwelling pre-frail and frail elderly, aged ≥65 years, with and without sarcopenia.
We observed that multi-domain physical, nutritional, and cognitive interventions among pre-frail and frail older adults were associated with favorable changes in sarcopenia and blood biomarkers underlying the muscle mass and physical functional response to intervention. As previously reported, the data are highly consistent with previous studies in showing that physical exercise alone or in combination with cognitive and nutritional intervention was most efficacious in improving muscle mass, lower limb strength, and gait speed. The physical exercise in this study was of moderate and gradually increasing intensity and well tolerated with high adherence rate (85%).
Perhaps unsurprisingly, there was limited effect observed with nutritional intervention delivered with a traditional oral nutrition supplement and not with a formulation with high content of leucine or whey protein or vitamin D, which have been shown in more recent studies to increase muscle mass and muscle function in sarcopenic and malnourished older patients.
Chronic low-grade inflammation associated with oxidative stress is believed to be a major underlying mechanism of aging and aging-related diseases including sarcopenia. Inflammatory markers such as CRP and IL-6 are reported to be associated with decreased muscle mass and strength, and the reduction of inflammation is believed to directly or indirectly ameliorate age-related muscle loss. In the present study, inflammatory levels are observed to be reduced especially by combined intervention, as evidenced by the significant drops in CRP and TNF-α levels. However, the levels of these inflammatory markers were not associated with sarcopenia status or reduction. Thus, the reduction of inflammation may not be the primary underlying mechanism of the response of sarcopenic elderly to lifestyle interventions.
Mesenchymal Stem Cell Therapy as a Treatment for Skin Aging
The term "mesenchymal stem cell therapy" covers a very broad range of cell sources and cell capabilities. Arguably the category needs to be thrown out and replaced with a more detailed taxonomy. The results of mesenchymal stem cell therapy in one clinic can be wildly different from those in another due to small differences in protocol, even given a similar source of cells.
Taken as a whole, this class of therapy appears to fairly reliably suppress chronic inflammation for a time, while unreliably provoking increased regeneration and tissue maintenance. Transplanted cells near all die rapidly rather than integrating into tissues, and results are thus achieved via the signaling generated for a brief time by the transplanted stem cells.
In this review paper, researchers discuss some of the evidence for mesenchymal stem cell therapies to improve structure and function in aged skin, which is an area of clinical practice in which one needs to follow references somewhat more carefully than is usually the case, given the sizable contingent at that end of the community that likes to play fast and loose with the truth.
Aged skin is highly associated with loss of function and structural degeneration. With aging, the skin naturally loses its collagen content and elastic fibers become deranged. Additionally, aged skin demonstrates an increase in oxidant activity, and an increase in the production of matrix metalloproteases (MMP), which are typically involved in matrix degradation. Additionally, exposure to UV light is known to promote premature aging of the skin, namely photoaging. Thus, rejuvenation therapies, which focus on the prevention and reversal of skin aging are in high demand in our society, which increasingly aims to maintain a youthful appearance and improve their health.
Adipose derived MSCs (AD-MSCs) have been gaining attention in skin antiaging therapy because of their efficient re-epithelization and secretion of several growth factors necessary for skin regeneration. In recent years, researchers observed histological and structural modifications in aged facial skin after the injection of expanded AD-MSCs, collected from fat removed by liposuction. Treatment with AD-MSCs caused an increase in elastic fibers in the superficial layer of the dermis and modified the collagen and reticular fiber networks, which became more arranged. Subsequently, AD-MSCs were observed to induce complete regeneration of solar elastosis in photoaged skin.
The transplantation of AD-MSCs leads to complete regeneration of dermal elastic matrix components, including oxytalan, elaunin, and elastin fibrillary networks. In solar-aged skin, the normal elastin matrix is usually lost, and AD-MSC-mediated treatment successfully reversed the inhibition of precursor molecules involved in neoelastinogenesis.
Another way to use AD-MSCs in antiaging therapy, in a "cell-free" method of treatment, is by using extracellular vesicles (EVs), which have several advantages over stem cells and their safety issues. Adipose-derived mesenchymal stem cells extracellular vesicles (AD-MSCs-EVs) have anti-photoaging potential and were analyzed as subcutaneous injections in photoaged mice models. The treatment resulted in a decrease in skin wrinkles and promotion of epidermal cell proliferation. Additionally, macrophage infiltration and reactive oxygen species (ROS) production were reduced, which inhibited MMP activation and collagen degradation.