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- Senolytic Treatment Improves Muscle Regeneration in Old Mice Only
- Plagl2 / Dyrk1a Gene Therapy Restores Youthful Behavior of Neural Stem Cells
- Cardiorespiratory Fitness Slows Structural Changes in the Aging Brain
- Towards More Broadly Effective Influenza Vaccines
- A Look Back at 2021: Progress Towards the Treatment of Aging as a Medical Condition
- Lower Hemoglobin Levels Correlate with Raised Mortality in Older People
- What is Known of the Reasons Why Aging Stem Cells Lose their Regenerative Capacity
- Novel Approaches to Protect the Heart Following Injury
- The Failure of Mitophagy as a Contributing Cause of Sarcopenia
- Frailty is a Risk Factor for Dementia
- Another Large Longevity-Focused Venture Fund in Europe
- Towards a Theory of Autophagy Thresholds for Optimal Lifestyle Choices
- The Chronic Inflammation of Aging Interferes in Muscle Metabolism
- Inflammatory Microglia Impede Myelination in the Aging Brain
- Red Meat Increases Cardiovascular Risk via Raised TMAO Production by the Gut Microbiome
Senolytic Treatment Improves Muscle Regeneration in Old Mice Only
Senescent cells accumulate with age. Researchers here provide evidence for yet another age-related decline to be added to the long list of issues in which this accumulation of senescent cells is an important contributing cause. In this case, the problem is the loss of regenerative capacity in muscle tissue that occurs with age. Can this be due to loss of stem cell activity? Past research has indicated that muscle stem cell populations are largely intact in old individuals, but increasingly quiescent and inactive. Removing senescent cells removes some portion of the inflammatory signaling characteristic of old age, and this signaling may be influential in the loss of stem cell function in many tissue types.
Equally, the loss of regenerative capacity may have more to do with changes in the timing of clearance of senescent cells during the process of tissue regrowth following injury. The immune system becomes less able to rapidly clear senescent cells in later life. There has been some concern that intermittent removal of senescent cells via senolytic treatment would impair wound healing, given that the short-term presence of senescent cells is involved in the intricate coordination of different cell types that is needed for regeneration. As this study shows, the benefits of removing senescent cells in this way outweigh the downsides, at least in the old mice. In young mice, removal of senescent cells is disruptive to wound healing.
The evidence here suggests that issues in aged muscle regeneration are caused in part by (a) the inability of the immune system to rapidly clear the senescent cells created during the healing process, and (b) senescent immune cells that enter the injured area. The aged environment may be forcing immune cells into senescence rather than allowing them to perform the usual pro-regenerative activities.
Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice
Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7 days or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7 days and 14 days following injury, suggesting they are infiltrating immune cells.
By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
Plagl2 / Dyrk1a Gene Therapy Restores Youthful Behavior of Neural Stem Cells
In today's open access paper, the authors report on a successful effort to restore youthful behavior in neural stem cell populations in aged mice. A lentiviral gene therapy to upregulate plagl2 and downregulate dyrk1a resulted in increased production of new neurons, to a pace normally seen in young animals, and cognitive function improved as a consequence. Like all stem cell populations, the activity of neural stem cells declines with age. A supply of new neurons that will integrate with existing neural circuits is necessary to maintain the function of the brain, particularly learning and recovery from the sort of small-scale damage that is inflicted on brain tissue over time, such as through the rupture of capillaries.
Thus the research community is very interested in finding ways to safely increase neurogenesis, the production of new neurons, in the aging brain. Beyond functional gains and resilience, it is hoped that increased neurogenesis can help in the recovery from serious brain injury, such as that caused by stroke. Another approach to this challenge is the reprogramming of supporting glial cells in the brain, turning them into neurons, though recent work in that part of the field has proven disappointing. It remains to be seen as to which of the various approaches will reach the clinic and use in human patients, and how long it will take to achieve that goal.
Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity
Aged neural stem cells (NSCs) are mostly dormant, and even when they are activated, they primarily produce astrocytes. Thus, aged NSCs lose their proliferative and neurogenic potential, leading to the cessation of neurogenesis. In this study, we showed that the iPaD (inducing Plagl2 and anti-Dyrk1a) lentivirus substantially rejuvenated the proliferative and neurogenic potential of NSCs in the aged brain. Clonal analysis by a sparse labeling approach as well as transcriptome analysis indicated that iPaD can rejuvenate aged NSCs (19-21 mo of age) to a level comparable with those at 1 or 2 months of age and successfully improved cognition of aged mice.
Once rejuvenated and activated by iPaD, aged dormant NSCs can generate, on average, 4.9 neurons but very few astrocytes in 3-week tracing. Furthermore, these activated NSCs were maintained for as long as 3 months in the aged brain, suggesting that active neurogenesis continues for an extended period of time after iPaD treatment. Nevertheless, iPaD-activated neurogenesis gradually declined. Furthermore, clonal analyses showed that 78.1% (9-month-old) and 81.7% (19-month-old) of iPaD-activated clones maintained RGL cells 4 week after activation, suggesting that ∼20% of activated NSCs are exhausted during this period. However, it is unknown whether this exhaustion is due to limitation of iPaD or loss of iPaD activity, and further analyses are requited to answer this question.
A recent study showed that resting NSCs, those once proliferated but returned to quiescence, are the major origin of active NSCs in the aged brain. This population comprises only 3%-5% of the total NSCs, while the other major population is dormant NSCs, which have never proliferated. Because the iPaD is able to activate 70%-80% of NSCs in the aged brain, it is likely that it mostly targets dormant NSCs, raising the possibility that the higher the infection efficiency of the iPaD virus, the more NSCs are activated to produce new neurons.
During aging, the gene expression and accessible chromatin landscapes change dynamically in NSCs. Transcriptome analysis showed that there are eight clusters of genes showing different expression patterns. Among them, clusters 2, 3, and 6 are of particular interest: In clusters 2 and 3, gene expression is down-regulated in aged NSCs compared with embryonic NSCs but up-regulated by iPaD, while in cluster 6, gene expression is up-regulated in aged NSCs but repressed by iPaD. Genes involved in cell proliferation are enriched in clusters 2 and 3, while genes involved in aging are enriched in cluster 6. In addition, chromatin-modifying genes are also enriched in clusters 2 and 3. These results suggest that iPaD can rejuvenate aged NSCs by up-regulating embryonic-high genes and repressing age-associated genes via modulation of chromatin accessibility. The detailed mechanism by which iPaD differentially regulates the chromatin structures remains to be analyzed.
Cardiorespiratory Fitness Slows Structural Changes in the Aging Brain
Today's open access paper discusses recent data on age-related changes in brain structure, assessed in older people with varying degrees of physical fitness, though all were described as inactive. Brain atrophy is characteristic of aging; loss of volume proceeds steadily year after year in the latter half of life, accompanied by chances in structure and distribution of tissues. This is one part of the processes that lead to loss of cognitive function and dementia. It is known that physical fitness, and the exercise needed to maintain that fitness, slows this progression.
Many different mechanisms are likely involved in the ways in which fitness can slow the aging of the brain. For example, exercise boosts BDNF levels, which encourage neurogenesis, the production of new neurons in the brain. Further, both exercise and the state of fitness improve blood flow to the brain, in the short term and the long term. Brain tissue requires a great deal of energy to perform its functions, and a flow of nutrients and oxygen is essential. That exercise can improve cognitive function very quickly, on the same timeframe as increased cerebral blood flow, suggests that the brain has evolved to operate at the upper limit of its energy supply. Any loss from the peak will affect tissue over the long term.
Investigating impact of cardiorespiratory fitness in reducing brain tissue loss caused by ageing
Late adulthood is marked by a host of physical changes and brain atrophy is one of the most ubiquitous. Specifically, after the age of forty, brain volume declines at a rate of about 5% per decade. Furthermore, ageing-related shifts in brain morphology are associated with concomitant declines in cognitive performance. As our population ages, there is paramount interest in strategies to potentially mitigate the brain tissue loss that occurs with ageing. In recent research, cardiorespiratory fitness (CRF) has been described to be neuroprotective in older adults. As CRF can be influenced through exercise intervention, there may be future potential for these therapies in mitigating neurodegeneration.
However, the influence of CRF on brain tissue has not been fully characterized quantitatively. Tissue atrophies in the ageing brain non-uniformly across multiple regions. Multiple studies have demonstrated that both ageing and decreased CRF are associated with non-uniform declines. Yet, prior studies investigating associations with CRF have not characterized differential atrophy and degeneration across the brain. First, conventional statistical methods comparing regional volumes and voxelwise metrics are insufficiently sensitive to the spatial interdependence in brain tissue, and its nonlinearity. Indeed, regional volumes have led to varying reports of the degree to which tissue shifts dependent on age and those dependent on CRF overlap. In contrast, new techniques that measure spatial variation in brain tissue as mathematical distributions can directly measure these diffuse, non-linear processes. Second, while regional volumes and voxelwise metrics are basic statistical descriptors, they do not correspond to any biophysical properties of brain tissue.
In recent work, the authors developed an automated approach to discover discriminant phenotypic patterns from brain images by directly measuring the spatial tissue distribution. This approach enabled biophysical properties of the brain to be modelled as mass transport. The technique is called 3D transport-based morphometry (TBM). This paper applies the novel TBM approach to extract the perturbations in brain phenotype statistically explainable by CRF. The goal of this research is to discover and visualize the shifts in brain tissue distribution that are most strongly associated with CRF in an automated manner using the TBM technique. Furthermore, this study aims to determine the degree to which the pattern of tissue distribution with higher CRF overlaps with the distribution of ageing-related losses.
In this study of 172 inactive older adults aged 58-81 (66.5 ± 5.7) years, cardiorespiratory fitness was determined by VO2 peak (ml/kg/min) during graded exercise and brain morphology was assessed through structural magnetic resonance imaging. After correcting for covariates including age (in the fitness model), gender, and level of education, we compared dependent tissue shifts with age to those due to VO2 peak. We found a significant association between cardiorespiratory fitness and brain tissue distribution. A strong statistical correlation was found between brain tissue changes related to ageing and those associated with lower cardiorespiratory fitness. In both cases, frontotemporal regions shifted the most while basal ganglia shifted the least. Our results highlight the importance of cardiorespiratory fitness in maintaining brain health later in life.
Towards More Broadly Effective Influenza Vaccines
Might it be possible to develop a vaccine that works on every strain of influenza, rather than going through a seasonal exercise of vaccination every year? Or at least many strains, rather than just a few? In today's research materials, scientists discuss a possible approach, identifying a novel part of the influenza virus to target, a part of the viral structure that may mutate less readily than the usual vaccine targets. Viruses mutate aggressively when they infect large population, a challenge to both vaccination and natural immunity. The immune system recognizes small parts of a virus, epitopes, and the epitopes most readily recognized are those that mutate to form new strains. This is why we are presently stuck with (a) the yearly death toll inflicted by influenza variants, and (b) the small chance of a much worse variant showing up at some point to produce an outcome to rival the 1918 pandemic.
The burden of infectious disease falls most heavily on the old. An age-damaged immune system responds poorly to many types of vaccination, and is in any case far less capable of mounting a defense against pathogens of all varieties, even given vaccination. Vaccination clearly helps in the case of influenza, but old people are remain vulnerable and exhibit the highest mortality as a result of infection. Arguably far greater effort in research and development should be directed towards the rejuvenation of the immune system rather than better vaccines: regrowing the thymus; regeneration of lymph nodes; restoring youthful hematopoietic function; and clearing damaged and misconfigured immune cells.
No more annual flu shot? Researchers find new target for universal influenza vaccine
In a typical year, influenza affects more than 20 million people in the United States and leads to more than 20,000 deaths. Vaccines against influenza typically coax the immune system to generate antibodies that recognize the head of hemagglutinin (HA), a protein that extends outward from the surface of the flu virus. The head is the most accessible regions of HA, making it a good target for the immune system; unfortunately, it is also one of the most variable. From year to year, the head of HA often mutates, necessitating new vaccines.
Researchers have designed experimental influenza vaccines to be more universal, spurring the body to create antibodies against the less-variable stalk region of HA. In the new study, a collaborative team of scientists characterized 358 different antibodies present in the blood of people who had either been given a seasonal influenza vaccine, were in a phase I trial for an experimental, universal influenza vaccine, or had been naturally infected with influenza. Many of the antibodies present in the blood of participants were antibodies already known to recognize either the HA head or stalk. But a collection of new antibodies stood out; the antibodies bound to the very bottom of the stalk, near where each HA molecule is attached to the membrane of the flu virion.
Researchers named this section of HA the anchor, and began studying it further. In all, the scientists identified 50 different antibodies to the HA anchor, from a total of 21 individuals. The antibodies, they discovered, recognized a variety of H1 influenza viruses, which account for many seasonal flu strains. Some of the antibodies were also able to recognize pandemic H2 and H5 strains of influenza in lab tests. And in mice, the antibodies successfully protected against infection by three different H1 influenza viruses.
Broadly neutralizing antibodies target a hemagglutinin anchor epitope
Broadly neutralizing antibodies (bnAbs) targeting epitopes of the influenza virus hemagglutinin (HA) have the potential to provide near universal protection against influenza virus infection. However, viral mutants that escape bnAbs have been reported. The identification of bnAb classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here, we report a distinct class of bnAbs targeting a discrete membrane-proximal anchor epitope of the HA stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with pandemic-threat H2 and H5 viruses. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of bnAbs that are widespread in humans.
A Look Back at 2021: Progress Towards the Treatment of Aging as a Medical Condition
Well, here we are again, at the end of another pandemic year, a year older and - hopefully - a year wiser and more knowledgeable. I said all that really needs to be said on the topic of COVID-19 as an age-related condition at the end of last year. We might hope that, given widespread vaccination, the pandemic will become a topic of diminishing importance as the year ahead progresses, even given the present round of variants, fears, and reintroduction of restrictions.
Advocacy for Aging Research
Have we finally made significant progress in convincing the world that aging is the cause of age-related disease, that greater longevity is highly desirable, and that the treatment of aging should long have been a priority? The war on cancer is 50 years old; we can learn from it, and we must, as the war on aging had better move faster than that.
Treating aging as a medical condition is no longer the fringe idea it once was, yet the anti-aging marketplace remains a pit of snake oil and a ball and chain holding back progress, too many people are talking about only modest gains rather than the goal of radical life extension, and the majority of medicine for late life conditions still attempts the impossible of extending life without extending health. Further, all too many people think of late life disability as unavoidable, and this causes them to doubt approaches to extend life span. Still, treating aging is now explicitly the goal of research into aging. While the popular media continues to do a terrible job in explaining in the field, and governments, despite lobbying efforts, are still stuck in yesteryear, this may well be a whole new era. People are asking: should we work to end aging?
There are more patient advocates and more scientists talking about this concept, and soon there will be many physicians focused on longevity. Perhaps at some point soon the first rejuvenation technologies, such as senolytics, become so obviously beneficial that people will stop talking about ethics and just get on with preventing the suffering caused by aging and age-related disease. Priorities in research and the world at large are still not appropriate for the harms done by aging, but at least some people think that we should be aiming high, running moonshot projects to produce new therapies that will make a real difference. There is a strong economic argument for major investment in aging research and the development of therapies. The cost of failing to aggressive pursue rejuvenation therapies, both financial and measured in suffering and death, is huge.
It is interesting to look back at a January post on what to expect in the longevity industry in 2021. Investment in the industry is certainly growing, and many funds are actively creating companies rather than waiting for companies to arise. There will likely be a range of longevity industry specific SPACs soon enough, given the popularity of that approach to taking companies public. Michael Greve launched a $300M expansion of his Kizoo fund, specifically aimed at rejuvenation biotechnology after the SENS model. Apollo Ventures launched a new $180M fund, and Korify Capital launched a $100M fund a couple of months later. Cambrian Biopharma raised another $100M for their efforts. An industry advocacy group has formed, the Longevity Biotech Association.
The number of biotech startups is growing, and in Europe as well as the US. Some are very well capitalized, such as NewLimit, launched with a sizable warchest to develop in vivo reprogramming therapies. Numerous companies are now working on approaches to treat mitochondrial aging. While more funding and more biotech startups are good things, many of these companies are working on less ambitious approaches, relating to stress response upregulation or similar alterations to metabolism, or unguided drug discovery that will most likely discover more metabolic tweaks that modestly slow aging in mice. Others intend to target only skin aging to use the less costly cosmetics regulatory pathway, or work in the supplement space for similar reasons. Examples include Gerostate Alpha, Genflow Biosciences, Yuva Biosciences, Elysium Health, and the Maximon companies. Would that more groups come to choose better projects to focus on!
Various updates were noted from other companies that have been working on their projects for the past few years: Calico, Lygenesis; Selphagy; BioViva announced results from a small gene therapy trial; IntraClear Therapeutics; Repair Biotechnologies (a few times); Cellvie; Elastrin Therapeutics; Oisin Biotechnologies; Insilico Medicine; Revel Pharmaceuticals; Rejuvenate Bio; Leucadia Therapeutics (a few times); UNITY Biotechnology.
I have been paying less attention to events this past year, given that so many were virtual only, and virtual events offer little in the way of networking opportunities. Still, a few notes from various sources: the Aging, Geroscience and Longevity Symposium; the 7th annual AARD and 8th annual AARD meetings, as that conference series forged ahead bravely, pandemic or no pandemic; and the 2021 Longevity Week in London.
There are plenty of interviews and profile pieces to be found out there, many in video form given the Foresight Insitute salons, Live Longer World podcasts, and OnDeck Longevity community. A few that I noted: investor Ronjon Nag; James Peyer of Cambrian Bio; Aubrey de Grey, formerly of SENS Research Foundation; George Church on his broad portfolio of ventures; some notes on Jim Mellon; a profile of Michael Greve; epigenetic clocks with Morgan Levine, Steve Horvath, and Vadim Gladyshev. Also a couple of book reviews to add to that list: Ageless and Lifespan.
The SENS Research Foundation continues to do well in year end fundraisers - don't forget to donate this year! The foundation conducts important work in the field of rejuvenation, advancing neglected but important projects needed to repair the damage of aging. Earlier this year they were the recipient of more than $20M in charitable donations in connection with a cryptocurrency launch, and are hiring more scientists. The Methuselah Foundation, meanwhile, literally finds itself with more resources than it can easily access or spend, hundreds of millions of dollars at the time of writing, a result of strange machinations in the cryptocurrency space. The foundation also announced a winner for their Vascular Challange competition. Lifespan.io has extended their crowdfunding efforts to running small human trials of simple therapies, starting with mTOR inhibitors. Hopefully more to come as this approach to moving the field forward gains support.
The Forever Healthy Foundation continues to turn out great analyses of available therapies as a resource for all interested parties. The Astera Institute's Rejuvenome project launched this year, a sizable philanthropic effort to perform useful life span studies in mice that academia and industry will not get to on their own. Another new organization offers the Impetus Grants for high risk high reward aging research. The Radical Life Extension Group are performing small human trials of simple potential therapies such as plasma dilution. The Longevity Science Foundation launched in Europe with a sizable committment to research funding. Last but not least, VitaDAO is applying a distributed organization structure to funding aging research and development, and seems off to a good start.
Senolytics and Other Senotherapeutics
Senescent cells are influential enough on aging that models of aging based solely on senescent cell accumulation produce decent predictions. Accumulation of senescent cells has a bidirectional relationship with immune aging: the immune system clears senescent cells, but is harmed by their presence and inflammatory secretions. Cellular senescence spreads through tissues once established in any one location, a phenomenon possibly mediated by neutrophils. Bcl-xL is one of many senolytic drug targets, and it is found to correlate with aspects of aging in late life, also a sign of the relative importance of cellular senescence in aging. Senescent cells may explain the inverse relationship between cancer and neurodegeneration. Researchers are beginning to put numbers to senescent cell counts by age, such as in the immune system.
The number of companies working on senolytic and other senotherapeutic therapies continues to increase, as does the variety of approaches to the selective destruction of senescent cells, or the suppression of their activities, or the prevention of senescence. Those approaches include: the use of silica nanoparticles; GLS1 inhibition; activation of invariant natural killer T cells; identifying and then targeting surface markers selective for the senescent state, with candidates such as B2M; activation of the NRF2 pathway; supplementation with procyanidin C1; fisetin, still overdue for confirmation of its senolytic capacity in humans; supplementation with dihomo-γ-linoleic acid; NANOG overexpression; acid ceramidase inhibition; inhibiting IKK/NF-κB activation; piperlongumine, which continues to be comparatively poorly researched. The research and development communities are still far too slow to start clinical trials for the many age-related conditions that might be successfully treated via elimination of senescent cells from aged tissues. Nonetheless, there are some signs of progress here, such as calls for trials in cancer patients, though not everyone in the cancer research community is wholehearted enthused. Senescent cells are both helpful and harmful in the context of shutting down cancer.
Data continues to roll in to support the use of senolytics in a very wide range of conditions, even though senescent cells are likely different by tissue, and early drugs variably effective by tissue. Just in the past year, and only those that I happened to notice and discuss, by no means a comprehensive list: vascular senescence in atherosclerosis (a number of groups are looking at this), and in general as a component of vascular dysfunction; neurodegenerative conditions, as senescent microglia are found in greater numbers in the brains of patients with neurodegenerative conditions such as Alzheimer's disease, and there is a good deal of supporting evidence for senolytics to be a useful treatment for Alzheimer's; senescent cells play an important role in chronic kidney disease and loss of kidney regeneration with age; several lines of work show that senescent cells harm the sympathetic nervous system; they contribute to fatty liver disease; COVID-19 severity in the aged is mediated in part by senescent cell burden, and a trial of fisetin is underway in this context; vulnerability to inflammatory conditions is in general increased by senescent cells, not just in the case of COVID-19; senescent cells are found in skin, and thus contribute to skin aging; cartilage damage in osteoarthritis is caused in part by senescent cells; cancer severity is mediated by the relationship between cancer cells and senescent cells, and senolytics may reduce precancerous lesions; liver aging is clearly caused in part by senescent cells, as is kidney aging; also diabetic retinopathy and pulmonary fibrosis, the subject of human trials and ongoing work by several research groups; fibrosis in general can be treated with senolytic strategies; the contribution of visceral fat to insulin resistance is mediated by senescent cells; retinal aging; senescent cells may slow bone fracture repair; age-related metabolic dysfunction; disc degeneration is slowed by senolytic treatment; cellular senescence may be the mechanism linking psychological stress with cognitive decline; temporomandibular joint degeneration is caused in large part by senescent cells; type 2 diabetes accelerates degeneration via an increased burden of cellular senescence; brain aging and neurodegeneration; osteoporosis; the higher risk of failure of transplantation of old organs; the age-related decline in neurogenesis; poor outcomes in stem cell therapies due to senescence in cultured cell populations; prevention of scarring in nerve injury; gliosis and tau aggregation in tauopathies such as Alzheimer's disease.
All this said, continual clearance of senescent cells, as opposed to intermittent clearance, is probably a bad idea, as these cells do serve useful purposes when present for the short term. Thus senolytic vaccines that encourage immune destruction of senescent cells are an interesting option, but may not the right path forward. Early life use of senolytics may also be harmful over the long term. A pleasant surprise is that senolytic therapy does in fact improve muscle regeneration following injury in old mice, indicating that the negative effects of slow clearance of senescent cells in old age outweigh the negative effects of clearing those cells during the regenerative process.
Surprisingly little progress has been made on cheap, simple ways to assess the burden of senescent cells. Many different approaches have been proposed, but none are yet easily available for clinical use. Measuring extracellular vesicles from senescent cells in urine is one such proposed assay, assessing ANGPTL2 levels in blood is another. Researchers have also suggested measuring certain fatty acids that enter the blood and urine when senescent cells die.
The NIH has launched SenNet, a major research initiative in the biochemistry of cellular senescence. There is more evidence these days for mTOR inhibitors as senotherapeutics, not killing senescent cells but preventing senescence via upregulated autophagy. Naked mole-rats apparently employ cholesterol metabolism to enable cells to resist senescence, though it remains to be seen as to what can be achieved with this knowledge. It turns out that all senescent cells have genomic damage, produced on the transition into the senescent state. A last thought for this section: is exercise a mild senotherapeutic, given the evidence for a reduced burden of cellular senescence, and how about similar data for calorie restriction? Color me dubious as to the usefulness of this designation. If we start describing exercise as a rejuvenation therapy, then our bar is set far too low.
Inflammation and Other Immune Aging
The adaptive immune system ages in its own way distinct from the aging of the innate immune system, including excessive T cell expansion, disruption of naive T cell quiescence, and detrimental interactions between T cells and fat tissue that produce inflammation. Thymic involution is a noteworthy component of adaptive immune aging, and the activities of dendritic cells in response to infection may be important in this process. Persistent infection with cytomegalovirus is also important in the decline of the adaptive immune system. Researchers see CD4+/CD8+ cell ratio as a useful biomarker of immune aging.
Every aspect of immune aging should be a high priority target for intervention. Some groups are looking at ways to suppress macrophage inflammatory signaling, such via upregulation of mitochondrial uncoupling in these cells. Age-associated B cells also contribute to chronic inflammation, and might be productively cleared from the body. Memory B cells, on the other hand, decline in number and should be restored. Researchers are investigating the cGAS-STING pathway, microRNA-92a inhibition, CD40L, TLR4, MG53, and CXCL9 as targets for the suppression of unwanted inflammation in connection with various conditions.
Regrowth of the thymus is an important goal, and a step towards a small molecule approach has been made with the identification of Rac1 inhibition as a possible target. Naked mole rats undergo little thymic involution with age, and actually have three thymi rather than just one; as with many aspects of this long-lived, slowly aging species, it is a question mark as to whether there is anything useful that can be accomplished in the near term with this information. The aging of lymph nodes, coordination sites for the immune response, may turn out to be similarly important in later stages of life, limiting the degree to which a restored supply of immune cells could increase immune function.
The aging of the immune system ties into most other issues in aging. Immunosenescence is clearly important in Alzheimer's disease, as noted by numerous sources, as is chronic inflammation in the brain, also the subject of numerous discussions. This is also true of vascular inflammation in the brain. Loss of neurogenesis in the aging brain is partly mediated by inflammatory signaling. Inflammation drives osteoarthritis. It also involves and negatively affects the behavior of macrophage cells, disrupting their normal function, is the major cause of pituitary gland aging, and contributes to osteoporosis. Further, it harms proteostasis throughout the body. Chronic kidney disease has a bidirectional relationship with inflammatory immune aging.
When it comes to treating immunosenescence, exercise has been shown to at least modestly improve matters, as it does for most aspects of aging.
Changes in hematopoiesis, and damage to hematopoietic stem cell populations, are critical parts of immune aging. The bone marrow niche is responsible for much of these harmful changes, and chronic infection some of the rest. Researchers have considered autophagy upregulation as an approach to improving hematopoiesis. Further, CDC42 inhibition continues to look like a promising approach to improve hematopoietic function in older individuals, with more results published this year on the use of CASIN as one of the candidate drugs - it also works to promote function in other aging stem cell populations. On a related note, researchers have shown that old hematopoitic stem cells do not regain their function in a young environment, which should steer thoughts on what sort of therapies might work.
For tissue engineering: esearchers have built thyroid organoids that can improve function in mice; early intervention with thin cartilage sheets can turn back osteoarthritis in animal models. The research community is working towards ways to produce universal cells that can be introduced safely into any patient, thereby greatly reducing the cost of cell therapies and tissue engineering.
Cell therapies for Parkinson's disease are moving forward only slowly. Cell reprogramming is being combined with prior scaffold techniques to produce muscle tissue regeneration. Muscle stem cell populations appear largely intact in old age, just inactive. Delivery of astrocyte progenitor cells helps with stroke recovery in mice. Autologous cell therapy improves outcomes in heart failure. Interestingly, stem cell therapy improves mitochondrial quality control. Transplanted retinal cells have been shown to integrate into a damaged retina. Stem cell therapy produces tendon regeneration. Stem cell therapies might be used to treat skin aging. It is by now well known that first generation mesenchymal stem cell therapies suppress age-related inflammation, and this is under consideration as a way to treat frailty, a condition strongly associated with chronic inflammation. A clinical trial of stem cell therapy for frailty was conducted successfully this year. It is possible that the death of transplanted cells is in fact the mechanism by which inflammation is suppressed in stem cell therapies.
Exosomes derived from stem cells offer a logistically simpler approach to therapy than the delivery of stem cells themselves. Exosome treatments have been showed to work in animal models: slowing aging in progeroid mice; treating disc degeneration; producing heart tissue regeneration; acting to reduce frailty in old mice.
Atherosclerosis kills a quarter of humanity via heart attack, stroke, and consequences of narrowed arteries. Preclinical atherosclerosis is widespread by age 50. At root, it is a condition caused by dysfunction in the macrophage cells responsible for clearing molecular waste from blood vessel walls. Atherosclerosis cannot yet be meaningfully reversed. Could selectively targeting the right inflammatory processes achieve that goal? Hypertension is also a contributing factor, altering arterial structure to accelerate atherosclerosis, illustrated by the point that successful control of blood pressure in later life produces a meaningful reduction in mortality. Mitochondrial dysfunction can also be argued to contribute, as can clonal hematopoiesis.
In other research into atherosclerosis and its consequences, heart attacks are more severe in sedentary individuals, and one of the consequence of a heart attack is raised harmful inflammation. Incidence of stroke is declining in later life, an outcome of the slow lengthening of life span year over year. Researchers achieved reversal of atherosclerotic plaques in mice by targeting antioxidants to the cell lysosome to clear oxidized LDL, an interesting result. Unfortunately, earlier research indicating that nattokinase supplementation can reverse plaque was not replicated in a more rigorous trial, though a lower dose was used. More work is yet needed on this topic. Hunter-gatherer populations with high levels of exercise exhibit low levels of cardiovascular disease and dementia; exercise certainly helps to reduce risk in other populations, which in turn means that a substantial fraction of cardiovascular disease is self-inflicted, the result of a sedentary lifestyle. A few other interesting research results: inflammatory macrophages contribute to the formation of aneurysms; autophagy is protective in heart aging, and perhaps a useful target for therapies to slow heart aging; adjusting the production of elastic proteins in the heart may compensate somewhat for the damage of aging.
The Human Microbiome
The gut microbiome becomes uniquely dysfunctional from person to person over the course of aging, though that process is slowed by calorie restriction. Similarly there is no one universal beneficial configuration of the microbiome. Mapping the age-related changes in the gut microbiome is an ongoing process, but still in its early stages. Does reduced tryptophan intake contribute to these age-related changes? The aging gut microbiome may contribute to age-related anabolic resistance and immune system dysfunction, and thus the onset of frailty. It may also cause problems in innate immunity. Equally, the immune system helps to garden the microbiome, and its age-related decline allows for pathological microbes to grow in number. Numerous other age-related conditions and detrimental changes are influenced by the gut microbiome, including loss of neurogenesis.
Restoration of a youthful microbiome is a field in its infancy. Fecal microbiota transplantation looks like a compelling, simple approach that may work well to restore a youthful microbiome, and thereby improve function. That includes its use as a treatment for neurodegeneration. Probiotics may also work, but there is some work yet to be accomplished in order for this to be the case. Intermittent fasting helps to beneficially alter the gut microbiome to some degree; it can reduce the contribution of the aging microbiome to hypertension, for example. Icariin supplementation improves the gut microbiome in old mice, and produces consequent health and functional benefits.
The gut microbiome recieves a lot of attention in the context of aging, but how important is the skin microbiome? That is a new question, in search of an answer. Meanwhile, the oral microbiome is thought to spread inflammation into the body via damaged gums, increasing risk of Alzheimer's disease and other conditions.
There is plenty of evidence for mitochondrial aging to contribute to age related conditions. Recent research that I noted this year covered a few such conditions: sarcopenia; Alzheimer's disease (mitochondrial dysfunction in Alzheimer's is a popular topic); atrial fibrillation; and immunosenescence. Much of mitochondrial dysfunction with age may stem from a loss of mitophagy, the quality control mechanism responsible for culling damaged mitochondria. There is some question over which of mitophagy or oxidative stress is the first cause, however. Loss of mitophagy can contribute to stem cell dysfunction and the aging of the brain, among many other issues.
A variety of approaches to improving mitochondrial function, some compensatory, some not, are under consideration: inhibiting complex I activity; delivery of mitochondrially targeted peptides such as elamipretide; telomerase gene therapy; D-glyceric acid supplementation; glutathione precursor supplementation; targeting prohibitins to promote mitophagy; mitochondrial transplantation is presently a hot topic and the goal of numerous initiatives, perhaps even with the goal of transplanting entirely artificial mitochondrial-like structures; targeting the mitochondrial permeability transition pore; and upregulation of mitochondrial uncoupling, if it can be achieved in a safe way.
I pay less attention to cancer research than I used to. I am mostly interested in approaches that can produce very broad anti-cancer therapies, those capable of being applied to most or all types of cancer without much new development per type. Reprogramming of cancer cells into normal somatic cells has been suggested as a path to cancer therapies. The most promising path to a universal cancer therapy is, I think, interference in telomere lengthening. Chimeric antigen receptor immunotherapies are performing well in comparison to the prior generation of chemotherapies and radiotherapies, but still require too much work to adapt to specific types of cancer. Nonetheless, researchers are now adding chimeric antigen receptors to immune cells other than T cells, such as natural killer cells, and making other improvements, such as triggered activation. The engineering of B cells to attack cancer cells is another, similar approach. Other approaches that caught my eye: YAP upregulation; manipulation of "don't eat me" markers abused by cancers, such as CD47; targeting TRIM28 as a way to inhibiting alternative lengthening of telomeres; finding ways to make cancer cells die rather than become senescent in response to cytotoxic therapies.
Cancer survivors have a shortened life expectancy, which may be due to an increased burden of cellular senescence as a result of cell-killing therapies.
Neurodegeneration and Damage to the Brain
There are a lot of interesting correlations in aging and neurodegeneration: visual decline correlates with Parkinson's disease, for example, as does loss of kidney function, and leakage of mitochondrial DNA into the cell cytosol. Hearing loss correlates with dementia - but also with physical impairment. Aortic stiffness correlates with cognitive decline, as does any degree of raised blood pressure. Increased activation of monocytes and macrophages appears in Alzheimer's disease patients. Gum disease correlates with neurodegenerative conditions and all-cause mortality. Reduced oxygen supply to the brain also correlates with dementia. In many cases it remains unclear as to whether causation is involved, or this is a case of underlying causes of aging producing multiple pathologies at the same time. Intriguingly, cataract surgery correlates with lower risk of dementia, which indicates that the mechanism must be that reduced sensory input due to blindness accelerates brain aging.
Neurodegeneration is linked with vascular dysfunction and reduced capillary density, a feature of aging receiving more attention these days. Amyloid may contribute to this reduction in capillary density. Loss of capillary density is in effect a hallmark of aging. The hippocampus operates at the very edge of capacity, and any reduction in the supply of oxygen and nutrients will cause loss of function. The lymphatic system of the brain is also a new point of focus in Alzheimer's disease. Separately, arterial stiffening correlates with structural damage to the brain, and particularly so in diabetic patients, as one might expect. There is an ongoing debate over whether persistent viral infections contribute to Alzheimer's disease - expect more years of this back and forth over the data. Viral proteins can assist in the spread of protein aggregates, making it more than a matter of raised inflammation.
The amyloid cascade hypothesis remains at the center of research and development for Alzheimer's disease, just as α-synuclein is central to Parkinson's disease, though a lot of effort is going into adjusting it of late. Is Alzheimer's a lifestyle disease? Perhaps, though likely not as much so as is the case for type 2 diabetes. Researchers are considering splitting Alzheimer's into four subtypes based on differences in pathology and progression. There was a sizable debate over the approval of the immunotherapy aducanumab, given the poor outcomes in patients despite effective clearance of amyloid-β. Improved approaches to this sort of immunotherapy are beneficial in animal models but will they do any better in humans? Is amyloid-β pathology due to the fact that the aggregates associated with Alzheimer's disease deplete soluble amyloid-β? Or is it that misfolded amyloid-β spreads within cells, and the aggregates outside cells are less important? Amyloid-β aggregation can degrade synaptic connections. Does the amyloidosis of Alzheimer's disease actually start in the liver in some cases, in the same way as Parkinson's synucleinopathy can start in the intestinal tissues? Researchers are now suggesting that there is a tipping point in amyloid-β aggregation after which Alzheimer's is inevitable.
Loss of myelin maintenance is important in cognitive decline, as is blood-brain barrier dysfunction, allowing harmful cells into the brain. The supporting glial cells of the brain can both help and harm the blood-brain barrier in aging. Cholesterol metabolism might be important in Alzheimer's disease, but exactly how this is the case is up for debate. A great deal of evidence points to microglial dysfunction in the development of neurodegenerative conditions; these cells become more inflammatory with age, but also lose beneficial functions. They may also be important in the spread of tau aggregates. This may be aggravated by persistent viral infection. In synucleinopathies, α-synuclein pathology may be spread via lysosomal transfer between glial cells.
Assays for the early stages of neurodegenerative conditions will likely soon improve greatly. Detecting misfolded amyloid-β in blood, for example. Functioning of the glymphatic system in clearing molecular waste from the brain is coming to be seen as important in brain aging.
When it comes to discussion of therapies: tau knockdown gene therapy does well in mice, and tau immunotherapy is so far performing somewhat better in human patients than is the case for amyloid immunotherapy; telomerase gene therapy has seen one small trial, and awaits more; B cell depletion produces benefits in Alzheimer's mouse models; similarly clearance of microglia appears beneficial, as does CD22 inhibition to improve the behavior of microglia; adding new photosensitive proteins to the retina to replace the function of lost photoreceptor cells; delivery of klotho is neuroprotective; ultrasound treatment can improve mouse memory; a plagl2 / dyrk1a gene therapy restored youthful neurogenesis in mice; amyloid-clearing immunotherapies continue to be a major focus of the clinical development community even though they are failing to improve patient outcomes following successful clearance; chondroitin 6-sulphate gene therapy restored memory function in old mice; transcranial direct current stimulation has the most consistent evidence of the many approaches to electromagnetic stimulation of the brain.
Lastly, exercise does help to improve function and slow neurodegeneration, a conclusion based on extensive data. Since exercise is essentially free, even modest results are cost-effective. Recent research suggests, however, that in mice at least there is a narrow therapeutic window for exercise to improve neurogenesis. This doesn't conform to the broader findings of increased neurogenesis and benefits to function, so it will be interesting to see how this area of research proceeds. As a final thought, some high functioning older people retain good memory and functional connections in the aging brain. Why? More work is needed on this topic.
Other Age-Related Molecular Waste
Much of the world on amyloid is focused on amyloid-β and Alzheimer's disease, but there are numerous other sorts of amyloid in the aging body. Treatment of transthyretin amyloidosis is a going concern these days, though there is definitely room for improvement on the first therapies that focus more on destabilizing the problematic transthyretin forms than on actively removing them. Transthyretin amyloidosis contributes to numerous issues in aging, with growing evidence for it to be important in heart disease. in other news, amyloid contributes to muscle aging. Transient AGEs are important in the chronic inflammation attendant to metabolic diseases such as diabetes because they trigger the receptor RAGE and consequent inflammatory signaling. This can contribute to disc degeneration.
Epigenetics and Cellular Reprogramming
Epigenetic changes in aging are a hot topic these days, particularly since the rise of partial reprogramming as a way to reset epigenetic changes characteristic of aging. The present consensus is that this is a promising path to therapies to treat aging and age-related degeneration. Reprogramming is the adaptation of the process that naturally takes place during embryogenesis to clear out damage and form the embryonic stem cells that give rise to a young body. One important unanswered question is whether the epigenetic reset can be separated from dedifferentiation into stem cells; it is highly desirable to only achieve the former of those two outcomes. Reprogramming has slowed aging in progeroid mice, and was also shown to improve muscle regeneration. A range of other interesting demonstrations have been produced in recent years, such as regeneration of damaged heart muscle.
Many different projects, some with sizable funding, are attempting to build rejuvenation therapies based on reprogramming. If the cancer risk can be controlled, this could be a beneficial therapy for older people. There is clearly a great deal of work ahead in moving from early animal studies to widespread clinical use, and many challenges to solve. Related to the concept of reprogramming is the idea of introducing developmental signaling into adults in order to spur greater regeneration, an approach still at an early stage.
Work on epigenetic clocks continues apace, with the number of different clocks expanding rapidly. Some researchers argue that more attention should be given to traditional measures of frailty. For preference, more of this effort and funding directed to the relentless development of new clocks should be directed towards validating and understanding the clocks that exist. Understanding how age-related damage and dysfunction maps to specific epigenetic changes is important. It will be hard to use the clocks to assess therapies without that, and there are already too many studies publishing clock data with no accompanying health data, a trend that is detrimental to progress. Elsewhere, researchers proposed the basis for a universal mammalian clock. The GrimAge clock continues to produce good results to show it is much improved over earlier clocks. Cardiovascular health correlate with a lesser epigenetic age acceleration as measured by clocks. Epigenetic age acceleration also correlates with loss of kidney function.
Diet and exercise can be used to reduce epigenetic age by a few years, and the effects of diet are distinct from those of exercise. Heterochronic parabiosis also reduces epigenetic age in mice. Lastly, epigenetic clocks are being used with some success to establish chronological age in species where that is challenging via other means, such as lobsters.
Fasting and Calorie Restriction
Intermittent fasting as a way to modestly slow the progression of aging is a popular topic these days, and more rigor is being applied to testing fasting as a form of therapy. For Parkinson's disease, for example. Short term fasting can improve numerous measures of immune function, and this is a basis for its use in cancer patients. There is some work underway to directly compare the results of intermittent fasting versus calorie restriction in humans, an exercise long overdue. Researchers are questioning the once-daily feeding pattern in mouse studies of calorie restriction, suggesting that it may be allowing fasting-like mechanisms to operate significantly. On a related note, dogs have been found to benefit from time-restricted feeding.
That aside, calorie restriction is well known to slow aging in numerous species, and every year the research community produces more examples of specific manifestations of aging that are beneficially affected by a lower calorie intake. Calorie restriction slows cognitive decline, muscle atrophy, and lowers blood pressure and cardiovascular disease risk. Calorie restriction is proposed as an adjuvant therapy for cancer patients, and may impact cancer and cancer risk through reduced growth signaling. Calorie restriction is better than intermittent fasting at slowing cancer in mice. Methionine restriction, triggering just one of the nutrient sensing pathways, improves cognitive function in mice. It also improves the microenvironment of the aging brain. Calorie restriction slows renal artery aging. It also improves stem cell function.
An intriguing question: how much of the benefit of a healthy, non-restricted diet is due to the effects of natural calorie restriction mimetic compounds? This could be answered by suitable studies, but that work has yet to be done. In general, calorie restriction mimetic compounds assessed to date compare poorly to the practice of calorie restriction.
Parabiosis and Plasma Dilution
Plasma dilution emerged from parabiosis studies, is being tested in formal and informal trials, and there is some reason to think that it may be worth persuing as a modestly effective way to reduce the impact of aging on inflammatory signaling and other aspects of metabolism. That said, there is evidence to suggest that it isn't the dilution, but rather the albumin that must be provided when blood is diluted. Meanwhile, work on parabiosis itself continues apace, as does work on transfusion based therapies. Researchers have found that transfusions from fit mice to sedentary mice produce benefits to health, in large part mediated by clusterin levels, while serum from young mice improves muscle regeneration in old mice.
This year, I published some results from a self-experiment with flagellin immunization to adjust the gut microbiome, and a protocol for running a self-experiment with Khavinson peptides for thymic regrowth. In other news, a paper was recently published on a self-experiment with a growth hormone releasing hormone gene therapy; adventurous and risky, given the side-effects of upregulating growth hormone. It makes for an interest read, given that reducing growth hormone is the common strategy to slow aging and extend life in animal studies.
I write short essay posts here at Fight Aging! less often than I used to; the pressures of time loom large. Here are a few from the past year, however.
- Request for Startups in the Rejuvenation Biotechnology Space, 2021 Edition
- In the Best of Plausible Futures, We Will All Be Occasional Cancer Patients
- Wanted: A Non-Profit to Run as Many Low-Cost Trials of Promising Treatments for Aging as Possible
Odds and Ends
As ever, some items resist easy categorization, but are nonetheless interesting enough to mention. There is prehaps less agreement on a definition of aging than one might think. The children of the 21st century will largely live to be 100 or more if present longevity trends continue, despite the fact that 7.2% of the world's deaths can be attributed to the spread of sedentary lifestyles, and little further gain in human life span is possible via environmental improvement. Yet we should remember that 95% of present centenarians are frail: rejuvenation therapies are much needed. The correlation between wealth and longevity likely does not have cultural or genetic causes.
Radiation hormesis continues to be a topic of interest. Does gum disease speed other aspects of aging via inflammation, as thought, or by oxidative stress, as recently proposed? Historical gains in life expectancy were not just a matter of reduced child mortality, but occurred at all ages. Only a subset of cells in visceral fat are responsible for the harms that it causes to health and metabolism. Age-related vision impairment correlates with all cause mortality in later life. There is a growing portfolio of projects targeting myostatin as a basis for muscle growth. That fullerenes might extend life in mammals has quite comprehensively failed to replicate, as many of us expected would be the case. Some researchers are working on a gene therapy platform specifically for skin rejuvenation. The Hallmarks of Aging are now so ubiquitous in the literature that it is possible to find people willing to critique them rather than just cite them.
ENH1 inhibition allows scarless healing of skin injuries in mice. Flies raised in a germ-free environment have some aspects of aging slowed. Disruption of elastin structures in skin is a big problem, as there is no good approach queued up at an advanced stage of research. It will likely require carefully programmed cells in order to produce the right structures for youthful function. Telomerase and follistatin gene therapies extend life in mice. Most small molecules shown to slow aging change the expression of extracellular matrix genes; is there anything to be learned from this? VEFG gene therapy slows the loss of capillary density and extends life in mice, which is interesting given that one might expect this to produce damaged vessels, as that is what happens in wet macular degeneration in the retina. Ribosomal improvements lower errors in protein synthesis and modestly extend life in short-lived species.
There is continued progress towards reversible cryopreservation of organs, and on balance cryopreservation has a bright future - the question is how long it will take for that future to arrive.
While it is worth remembering that the demographic data on aging at very advanced ages is shaky at best, any number of novel views and models of aging are being put forward these day: the role of rate-limiting processes; a proposed staging system for aging in the clinic; aging as an emergent phenomenon; borrowing particle physics concepts to model aging; the tumor suppressor theory of aging; the adaptive-hitchhike model of the evolution of long-lived species; aging as a consequence of the colonization of land; a tripartite view of aging; the evolutionary layering of the hallmarks of aging; that compression of morbidity is in part the result of a failure to adequately treat the oldest people; the importance of the exponential mortality curve and what it tells us about aging; half of the gains in longevity since the 1960s are the result of technological progress rather than public health measures such as suppression of smoking; the expectation that the upward trend in life expectancy will increase in the future. Is thinking of aging as a contagious process in the body a good model for the way in which failing systems interact? Lastly, the hyperfunction theory of aging remains an at times confusing model, in need of clarification from those who argue for it.
People sometimes ask me why I am enthused by senolytics, and very bullish on accelerating the path to further trials and widespread use of the existing senolytic treatments like the dasatinib and quercetin combination. Just take a look at the year of references earlier in this post, linking senescent cells to pathology and their clearance to reversal of that pathology, dozens of papers and studies that I just happened to notice in passing this year. Or look at a similar wall of links to promising results from the end of last year. They are by no means comprehesive lists, only the work that caught my eye. The clearance of senescent cells produces results in animal studies that are far and away superior to any other approach tried to date when it comes to the rapid reversal of age-related disease.
Lower Hemoglobin Levels Correlate with Raised Mortality in Older People
Anemia is a lowered level of red blood cells and hemoglobin, leading to a diminished supply of oxygen to tissues and thus degraded function throughout the body. The anemia of aging, like all issues in later life, is a gradual onset, a sliding scale of dysfunction with an arbitrary line in the sand as how low hemoglobin must fall for it to be formally considered a medical condition. There are consequences prior to that point of course, as the study data here illustrates. The relationship between lower hemoglobin levels and higher mortality is linear. It is, however, an open question as to how much of this relates to downstream consequences of lower hemoglobin levels and how much is a case of individuals with a greater burden of molecular damage and dysfunction tending to have lower hemoglobin levels.
An increase in life expectancy has emphasized anemia as a public health concern because of the associated healthcare needs and financial burden it incurs. Anemia is common among older adults with the estimated prevalence of 17% among individuals aged ≥65 years. A large cohort study has found that the prevalence of anemia increased with age from 4 to 6% in those aged 65-69 years to 13-14% in those aged ≥85 years. Anemia has been associated with a range of adverse events including falls, cognitive deficits, hospitalization, and mortality among older adults.
Anemia has been defined as hemoglobin (HB) concentrations of less than 12.0 g/dL and 13.0 g/dL in women and men, respectively. Some studies have reported that relatively lower HB concentrations were predictors of increased risk of mortality, which were due to decreased oxygen carrying capacity causing left ventricular hypertrophy and ischemia. More recently, several prospective cohort studies have indicated that a non-linear association exists between HB concentrations and all-cause mortality. Anemia may be prevalent in the general population, particularly in older adults. The effect of HB concentrations is associated with infection, autoimmune disease, and chronic kidney disease. In the current study, we aimed to evaluate the relationship between HB concentrations and all-cause mortality among 1,785 older adults aged ≥65 years form Chinese longevity regions, using community-based cohort data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).
In total, 999 deaths occurred during a median follow-up of 5.4 years from 2011 to 2017. Analysis found no non-linear association between HB concentrations and all-cause mortality after a full adjustment for covariates among the older adults form longevity regions. The risk for all-cause mortality was significantly higher in the groups with HB concentration of less than 11.0 g/dL (hazard ratio: 1.37) and 11.0-12.0 g/dL (hazard ratio: 1.25); the risk of all-cause mortality was significantly lower in the groups with HB concentration greater than 14.0 g/dL (hazard ratio: 0.76) compared with the reference group (13.0-13.9 g/dL). This HB concentrations were found to be inversely and linearly associated with all-cause mortality.
What is Known of the Reasons Why Aging Stem Cells Lose their Regenerative Capacity
Declining stem cell function is undoubtedly an important contribution to degenerative aging and age-related mortality. Tissues require the supply of new somatic cells that is generated by stem cells in order to replace losses, repair damage, and maintain function. Unlike stem cells, somatic cells are limited in the number of times they can divide. Turnover of somatic cell populations is a central aspect of near all multicellular life, and the small populations of tissue-specific stem cells are vital to continued function in an environment in which somatic cells must be periodically replaced. The goal of human rejuvenation will require the restoration of youthful stem cell function, through some combination of replacement, alteration of cell behavior, or repair of damage.
Stem cell exhaustion is the result of multiple types of aging-associated damages and it is one of the phenomena responsible for tissue and organismal aging. Many mammalian tissue-resident stem cells display a substantial decline in replicative function as they mature. The renewal ability of human tissues declines with aging of stem cells altering their capacity to differentiate in different types of cells. Moreover, age-related loss of self-renewal in stem cells leads to a reduction in stem cell number. Nevertheless, it may be possible to generate therapeutic approaches to age-related diseases based on interventions to delay, prevent, or even reverse stem cell aging.
Understanding how stem cells age may help understanding the normal aging process at the organ level, specifically in tissues with continuous regeneration. These processes are influenced by various cell-intrinsic and cell-extrinsic pathways. Indeed, recent discoveries have revealed a complex interaction among cell-intrinsic, environmental, and systemic signals linked to stem cell function loss during aging.
Researchers have worked to understand the main mechanisms with in vitro and in vivo experiments. The principal causes of stem cells aging are accumulation of toxic metabolites, DNA damage, proteostasis, mitochondrial dysfunction, proliferative exhaustion, extracellular signaling, epigenetic remodeling, and loss of quiescence. Many of these aging mechanisms are in common with differentiated cells but stem cell exhaustion, or the quantitative and qualitative loss in stem cell function with time, has a more important impact on tissue aging compared to differentiated cells and has been postulated as one of the aging causes. Adult stem cells perform a critical function in tissue homeostasis by repairing and regenerating tissues throughout life. They maintain practically all tissues and organs, including the forebrain, bone, and muscle, and stem cell exhaustion, defined as a drop in stem cell number and function, is documented in essentially all tissues and organs maintained by adult stem cells. Furthermore, age-related alterations in hematopoietic stem cell differentiation result in fewer adaptive immune cells being produced.
Understanding how stem cell aging affects distant tissues and overall health span is just the tip of the iceberg. This line of research is important because it lays the groundwork for stem cell-based treatments to help people live longer lives. Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases.
Novel Approaches to Protect the Heart Following Injury
Researchers here discuss potential approaches to protect the heart from scarring and loss of function following a heart attack: senolytics to clear senescent cells; restoration of mitochondrial function; induction of telomerase activity; and inhibition of inflammatory signaling. Removing the cause of heart attacks by finding a cure for atherosclerosis, a way to reverse the fatty lesions that narrow blood vessels and weaken blood vessel walls, would be preferable to finding better ways to fixing the damage after the fact. But there will always be some call for ways to improve the regenerative capacity of an injured heart.
The hallmarks of myocardial aging may account for the reduced tolerance against myocardial ischemia/reperfusion injury in preclinical studies and thus, understanding mechanisms of myocardial aging may enable the development of new and effective therapies to reduce cardiac damage after myocardial infarction (MI) in the context of aging.
Senescent cells increase in aged tissues, which has been associated with the progression of age-related diseases. In this context, senescence markers are augmented in aged cardiomyocytes, which has been linked to higher risk of cardiovascular diseases. Senolytics are agents that can selectively target pro-survival proteins of senescent cells, inducing cell death. Regarding the heart, there are three major senolytics that have been widely studied in vivo and in vitro; Dasatinib, Quercetin, and Navitoclax. These senolytics have been shown to improve vascular function. Importantly, a study showed that oral administration of navitoclax to aged mice before in vivo myocardial infarction reduced mortality, as well as age-related myocardial remodeling and improved left ventricular function.
The mitochondria have been identified as an important target to reduce myocardial ischemia/reperfusion injury in the aged heart. The mitochondria in aging cardiomyocytes shows elevated ROS production, higher fragmentation and reduced biogenesis, thus producing mitochondrial dysfunction, which can contribute to the increased susceptibility of the aged heart to ischemic injury. Therefore, therapies targeting the mitochondria are an attractive area of research in cardioprotection.
During MI, a pathogen/antigen-independent inflammatory response, known as sterile inflammation, takes place. Due to the rupture in the cellular structure that occurs during MI, damage-associated molecular patterns (DAMPS) mediators are released and are recognized by pattern recognition receptors (PRRs), which in turn mediate the initiation of the inflammatory response. NLPR3 inflammasome is a multiprotein complex formed by the activation of PRRs, thereby increasing the production and release of proinflammatory cytokines via activation of caspase-1. Interestingly, pharmacological inhibition of caspase-1 reduced the infarct size in isolated rat hearts. Also, caspase-1 inhibition was also shown to provide additional protection when combined with remote ischemic preconditioning in rats subjected to in vivo myocardial infarction.
Telomeres are repeated hexanucleotide sequences at the end of eukaryotic chromosomes. Their presence is associated with DNA protection during cell division. Division of the cell as well as oxidative stress shortens these structures, leading the cell to a senescent state or apoptosis. Telomere length has been associated with coronary artery disease and therefore, it has been proposed as a biomarker for cardiovascular diseases. Telomerase is a key regulator of telomere length and integrity and as such, has gained attention for its potential benefits in age-related cardiovascular diseases. For instance, absence of telomerase has been associated with increased susceptibility to ischemic injury. By the same token, overexpression of telomerase can confer cardioprotection in mice hearts.
The Failure of Mitophagy as a Contributing Cause of Sarcopenia
Here, researchers discuss the role of mitochondrial quality control in sarcopenia. Sarcopenia is the name given to the later stages of the loss of muscle mass and strength characteristic of aging. Muscle is an energy-hungry tissue, and the age-related decline in mitochondrial activity is therefore likely a contributing factor in this progressive loss of function. Mitochondria are the power plants of the cell, responsible for generating the ATP molecules that store chemical energy needed to power cellular processes. Every cell contains a herd of hundreds of mitochondria, which are removed and recycled when they become worn or broken by the quality control process of mitophagy. Unfortunately mitophagy becomes less efficient with age, for reasons yet to be fully explored, but which are likely connected to changes in mitochondrial dynamics.
Mitochondria have strong impacts on the maintenance of cellular viability, including ATP production, oxidative phosphorylation (OXPHOX) homeostasis, calcium buffering, and apoptosis. Therefore, healthy quality control is crucial for the preservation of intracellular homeostasis of muscle cells with aging. The mitochondrial quality control (MQC) includes mitochondrial proteostasis, biogenesis, dynamics and autophagy. Orchestrated mechanisms contain several cellular factors and signaling pathways to ensure the integrity of mitochondria. Mitochondrial biogenesis is responsible for the generation of new mitochondria through the synergistic interaction of the nuclear and mitochondrial genes; mitochondrial dynamics is achieved by continual transformation between fusion and fission to eliminate the accumulation of unhealthy mitochondria; mitochondrial autophagy (mitophagy) is a process of selective removal of the hypofunctional and damaged mitochondria. Adverse alternations in the quality control mechanisms may lead to mitochondrial dysfunction, which can further contribute to muscle wasting and even sarcopenia.
The incidence rate of sarcopenia in the mid-life and elderly population varies according to different age, operational definitions, regions and ethnicities. A number of epidemiological studies have shown that the prevalence of sarcopenia gradually increases with age. It is conservatively estimated that 5%-13% of elderly individuals aged 60-70 years are suffering from sarcopenia. The numbers increase to 11%-50% among those aged 80 or above. Since the number and proportion of the global aging population is rapidly growing, the socio-economic burden of individuals and society may increase due to higher prevalence of sarcopenia. Sarcopenia was formally recognized as a disease in 2016, which attracted additional attention for this degenerative disease. Physical activity is recommended as the primary treatment for sarcopenia to improve muscle strength and mass, although no specific drugs have been developed with therapeutic effects in sarcopenia. In this review, we summarize the potential mechanisms of mitochondrial dysfunction with an emphasis on promising therapeutic interventions to prevent and ameliorate sarcopenia during aging.
Frailty is a Risk Factor for Dementia
Age-related frailty is characterized by physical weakness and chronic inflammation, but this is the visible tip of the iceberg. Chronic inflammation accelerates much of the dysfunction of aging. As researchers note here, this includes neurodegenerative processes that lead to dementia. Reducing frailty in the population will therefore likely lead to a reduction in dementia incidence. The most plausibly useful lines of work on frailty therapies at present focus on ways to reduce the chronic inflammation of aging, from elimination of senescent cells and their pro-inflammatory secretions to ways to selectively suppress inflammatory signaling.
Researchers worked with data from more than 196,000 adults aged over 60 in the UK Biobank. They calculated participants' genetic risk and used a previously-developed score for frailty, which reflects the accumulation of age-related symptoms, signs, disabilities and diseases. They analysed this alongside a score on healthy lifestyle behaviours, and who went on to develop dementia. "We're seeing increasing evidence that taking meaningful action during life can significantly reduce dementia risk. Our research is a major step forward in understanding how reducing frailty could help to dramatically improve a person's chances of avoiding dementia, regardless of their genetic predisposition to the condition. This is exciting because we believe that some of the underlying causes of frailty are in themselves preventable. In our study, this looked to be possible partly through engaging in healthy lifestyle behaviours."
Over the 10-year UK Biobank study period, dementia was detected via hospital admission records in 1,762 of the participants - and these people were much more likely to have a high degree of frailty before their diagnosis compared with those who did not develop dementia. The importance of preventing or reducing frailty was highlighted when the researchers examined the impact of genetic risk in people with different degrees of frailty. Genetic risk factors exerted their expected effect on risk of dementia in study participants who were healthy, but genes were progressively less important in study participants who were the most frail. In those frail study participants, risk of dementia was high regardless of their genes.
Compared with study participants with a low degree of frailty, risk of dementia was more than 2.5 times higher (268 per cent) among study participants who had a high degree of frailty - even after controlling for numerous genetic determinants of dementia. Study participants who reported more engagement in healthy lifestyle behaviours were less likely to develop dementia, partly because they had a lower degree of frailty.
Another Large Longevity-Focused Venture Fund in Europe
A sizable amount of venture capital has emerged to support the longevity industry over the last year. The Korify Capital fund noted here is the latest of a series of longevity-focused funds to be announced. Whether or not this fund will invest in a sizable number of useful efforts remains to be seen, though their first investment is on the better end of the small molecule discovery space. There is all too much investment in the development of supplements, calorie restriction mimetics, and other line items that may be a part of the longevity industry, and may well produce a return on investment, but which at the end of the day will do little to change the shape and length of a human life span. That is the nature of the beast; even for funds in which the principals are very interested in the outcome of greatly extending the healthy human life span, the limited partners that provide the funding care little for anything other than a safe return on investment. It is their interests that ensure that unambitious, incremental, lower risk projects are pursued to a greater extent than is merited.
Longevity and mental health biotechs take note: Korify Capital is putting together a $100 million venture fund targeting your space and is looking to build a portfolio of 15 to 20 companies across Europe, the U.S. and Israel. The targeted $100 million investment vehicle, which is expected to close around the middle of next year, is the first fund of Korify, the international venture arm of Swiss family office Infinitas Capital. Infinitas is active in multiple areas outside of biotech, notably real estate, but has been tracking advances in aging and mental health research and has decided the time is right to enter the space.
The Korify principals identify COVID-19 as an accelerant, both because it has increased the interest of generalist investors in longevity and because it could spur innovation in the historically moribund mental health sector. With large biopharma companies pulling back from central nervous system research, Korify sees room for smaller biotechs to build on academic progress, creating investment opportunities for the new VC fund. "There's not like a couple of dominant companies that just own the space. Rather, there's a lot of disruption happening at the smaller scale, in smaller biotech companies, that are very lucrative to invest in and very interesting from an investor's perspective."
Korify plans to invest in 15 to 20 such biotechs, with a focus on later-stage platform companies. That focus is evident in Korify's decision to make Cambrian Biopharma its first investment. Cambrian, which exited stealth in February, has disclosed $160 million in financing this year to advance a pipeline of 14 drug candidates designed to target biological drivers of aging. "We like their approach of being very diversified, with multiple shots on multiple targets. They also are very aware of the current regulatory systems that are in place. We don't really have any solid longevity biomarkers, so their strategy is set up in a way that they can get there with the current FDA framework."
Towards a Theory of Autophagy Thresholds for Optimal Lifestyle Choices
The authors of this open access paper take an interesting position on the use of lifestyle choices to slow aging. In their view the most important outcome is an increase in the efficiency of autophagy, and since we know very little about the thresholds required to stimulate autophagy effectively, we in fact know very little about how to make optimal lifestyle choices. Autophagy is the name given to the collection of cellular maintenance processes responsible for removing damaged proteins and structures in the cell, recycling them into raw materials for other uses. Research into the biochemistry of the beneficial calorie restriction response suggests that upregulation of autophagy is required for improved health and extended lifespan. Additionally, improved autophagy is a feature of many of the interventions that slow aging in laboratory species.
This narrative review highlights the studies that explain regular physical exercise and sleep patterns, as well as fasting, and autophagy as a strategy for healthy longevity and well-being. Currently, any of these methods have been used for achieving healthy longevity and well-being within different stage of life from childhood to old-age; however, focusing on combination of all four methods instead of using just one should be the primary aim in the process of reaching healthy longevity and well-being in full capacity. Despite all the advances that have been made to create adequate physical exercise programs, sleep patterns, or nutritional protocols, the relation between different types of fasting, nutritional supplementation and regular physical exercise and sleep patterns have not yet been satisfactorily resolved to cause the best effects of autophagy and, therefore, healthy longevity and well-being.
Previous research gave some guides how to create adequate protocols to reach the best effects of autophagy, but no studies answered the most important questions how to recognize the autophagy threshold and how to use various factors such as fasting and calorie restriction as well as regular physical activity and regular sleeping to stimulate autophagy and decrease the autophagy threshold. In this way, since there are no previous studies, the first future study should create a theory of autophagy threshold, while the rest of future studies should be clinical trials that would confirm independent and joint positive effects of regular physical exercises and sleep patterns, as well as fasting and autophagy on healthy longevity and well-being.
The Chronic Inflammation of Aging Interferes in Muscle Metabolism
Researchers here discuss some of the details of the disruption of muscle metabolism caused by inflammation in aging. With advancing age, the immune system becomes ever more overactive and dysfunctional, reacting to signs of cellular damage and the pro-inflammatory signals of senescent cells. This immune activity is harmful to tissue function throughout the body. In the case of muscle tissue it speeds the loss of muscle mass and strength that occurs with age, contributing to sarcopenia and frailty.
Aging is associated with the development of chronic low-grade systemic inflammation (LGSI) characterized by increased circulating levels of proinflammatory cytokines and acute phase proteins such as C-reactive protein (CRP). Collective evidence suggests that elevated levels of inflammatory mediators such as CRP, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) are correlated with deteriorated skeletal muscle mass and function, though the molecular footprint of this observation in the aged human skeletal muscle remains obscure.
Based on animal models showing impaired protein synthesis and enhanced degradation in response to LGSI, we compared here the response of proteolysis- and protein synthesis-related signaling proteins as well as the satellite cell and amino acid transporter protein content between healthy older adults with increased versus physiological blood hs-CRP levels in the fasted (basal) state and after an anabolic stimulus comprised of acute resistance exercise (RE) and protein feeding.
Our main findings indicate that older adults with increased hs-CRP levels demonstrate (i) increased proteasome activity, accompanied by increased protein carbonylation and IKKα/β phosphorylation; (ii) reduced Pax7+ satellite cells; (iii) increased insulin resistance, at the basal state; and (iv) impaired S6 ribosomal protein phosphorylation accompanied by hyperinsulinemia following an acute RE bout combined with protein ingestion. Collectively, these data provide support to the concept that age-related chronic LGSI may upregulate proteasome activity via induction of the NF-κB signaling and protein oxidation and impair the insulin-dependent anabolic potential of human skeletal muscle.
Inflammatory Microglia Impede Myelination in the Aging Brain
Myelin sheathing of the axons connecting neurons is essential to the correct function of the nervous system. It is maintained by oligodendrocyte cells, but as noted in this open access paper, the maintenance of myelin is disrupted by the growing inflammation that accompanies aging. In the brain, microglia are innate immune cells that are responsible for a great deal of this inflammation. Some become senescent while others are overactive, made aggressive and inflammatory by the presence of damage and molecular waste in brain tissue. Removing senescent cells in the brain is a promising strategy to reduce the scope of age-related neuroinflammation, but other approaches will be needed as well to reduce inflammatory activity to youthful levels.
Extensive brain atrophy is a characteristic manifestation of aged brain. White matter degeneration is accompanied by encephalatrophy, leading to irreversible neurological and cognitive impairments. Remyelination is a natural protective and regenerative process that will be initiated in response to the degeneration of white matter. It is a complex process involving oligodendrocyte precursor cell (OPC) activation, migration, differentiation, and maturation to be oligodendrocytes (OLGs). Accumulating evidence indicates that remyelination is disturbed in the aged brain. However, a clear understanding of the effect of brain aging on the process of remyelination is still lacking.
Brain aging heightened the neuroinflammatory profile of the cerebral microenvironment, which activated microglia by attributing it to aging-related changes in remyelination. Previous studies have reported that activated microglia secrete a heterogeneity array of signaling molecules, including nitric oxide, reactive oxygen species, Il-6, Il-1β, and tumor necrosis factor (TNF), contributing to myelin damage and hindering proliferation or differentiation of OPCs. However, other studies indicated that activated microglia could promote OLG survival or OPC differentiation by releasing several regenerative factors including Igf-1, Igf-2, galectin-3, activin-A, and Il-1β, and clearing myelin debris.
These diverse results may be driven by the heterogeneous subpopulation of microglia, OLGs, and OPCs. Specific subgroups of OLGs and OPCs in different states may respond inconsistently to the stimulus of activated microglia. In addition, our previous study revealed that there were six subgroups of microglia with divergent functions in aged brain. A unique type of highly activated microglia was observed in aged mice only, with functional implications in immuno-inflammatory response. It remains poorly understood how this specific age-related subgroup of microglia effect on remyelination in aged brain. The exact mechanism of aged microglia in regulation of distinct subgroups of OLGs and OPCs needs to be determined.
In the present study, we aimed to explore the subclusters of OLGs and OPCs by analyzing the single-cell RNA sequence (scRNAseq) data of both young and aged brains. Oligodendrocytes were observed to up-regulate several senescence associated genes in aged brain. Four clusters of oligodendrocyte precursor cells (OPCs) were identified in both young and aged brains. The number of those OPCs in basal state was significantly increased, while the OPCs in the procedure of differentiation were immensely decreased in aged brain. Furthermore, it was identified that activated microglia in the aged brain released inflammatory factors to suppress OPC differentiation. Stat1 might be a potential target to transform senescent microglia into tissue repair type to promote oligodendrocyte generation.
Red Meat Increases Cardiovascular Risk via Raised TMAO Production by the Gut Microbiome
More research into aging and the gut microbiome is taking place these days. A greater investment into this line of research will, as illustrated here, likely lead to a greater knowledge of the mechanisms underlying the known correlations between diet and age-related conditions. That red meat consumption increases cardiovascular risk is quite well established from epidemiological data, and here researchers outline their view of why this happens. One might contrast this with the present consensus, which is that red meat consumption increases lipid levels in the bloodstream, thereby accelerating atherosclerosis and consequent cardiovascular mortality.
In a previous series of studies, researchers found that a byproduct that forms when gut bacteria digest certain nutrients abundant in red meat and other animal products - called TMAO (trimethylamine N-oxide) - increases the risk of heart disease and stroke. The latest findings offer a more comprehensive understanding of the two-step process by which gut microbes convert the nutrient carnitine into TMAO, an atherosclerosis- and blood clot-promoting molecule, following the ingestion of a red meat-rich diet.
Dietary carnitine is converted into TMAO in the gut through a two-step, two microbe process. An intermediary metabolite in this process is a molecule called γBB (gamma-butyrobetaine). Multiple gut microbes can convert dietary carnitine to γBB, but very few can transform the molecule to TMA, the precursor to TMAO. "In omnivores, Emergencia timonensis is the primary human gut microbe involved in the transformation of γBB to TMA/TMAO. Conversely, long-term vegetarians and vegans have very low levels of this microbe in their gut and therefore have minimal to no capacity to convert carnitine into TMAO."
The researchers studied the relationship between fasting plasma γBB levels and disease outcomes using samples and clinical data collected from nearly 3,000 patients. Higher γBB levels were associated with cardiovascular disease and major adverse events including death, non-fatal heart attack or stroke. To understand the mechanistic link between γBB and the observed outcomes in patients, the researchers studied fecal samples collected from mice and patients, as well as preclinical models of arterial injury. They found that introducing E. timonensis completes the transformation of carnitine to TMAO, elevates TMAO levels, and enhances blot clot potential.