Fight Aging! Newsletter, April 8th 2024

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A Stem Cell Secretome Treatment Improves Measures of Health in Old Mice

The stem cell therapy industry is evolving. There are a few reasons for this. Firstly, cells remain hard to work with as a basis for therapy, and the level of standardization expected by regulators is very challenging to achieve, even for companies with very deep pockets. In the wilder world of stem cell therapies obtained via medical tourism, outcomes vary broadly from clinic to clinic and patient to patient for reasons that remain unclear. Secondly, stem cell transplantation produces benefits to aged patients primarily via the signaling produced by transplanted cells in a short time prior their destruction, rather than through any other activity of those cells.

Given these points, there is a slow shift away from using cells and towards the use of cell products such as harvested extracellular vesicles or, as in today's open access paper, the secretome of all molecules that exit the cell into extracellular medium, not just those encapsulated in vesicles. Immunis Biomedical is the company involved in the work reported here, working towards the clinical use of stem cell secretome therapies. Primarily this work involves standardization of cell lines and consistency of the resulting harvested secretome to a degree that will satisfy the regulators. Cells are still hard to manage, but compressing down that management into only the centralized process of manufacturing the therapy makes the goal attainable with a reasonable amount of funding.

Stem cell secretome treatment improves whole-body metabolism, reduces adiposity, and promotes skeletal muscle function in aged mice

Aging coincides with the progressive loss of muscle mass and strength, increased adiposity, and diminished physical function. Accordingly, interventions aimed at improving muscle, metabolic, and/or physical health are of interest to mitigate the adverse effects of aging. In this study, we tested a stem cell secretome product, which contains extracellular vesicles and growth factors, cytoskeletal remodeling factors, and immunomodulatory factors. We examined the effects of 4 weeks of 2×/week unilateral intramuscular secretome injections (quadriceps) in ambulatory aged male C57BL/6 mice (22-24 months) compared to saline-injected aged-matched controls.

Secretome delivery substantially increased whole-body lean mass and decreased fat mass, corresponding to higher myofiber cross-sectional area and smaller adipocyte size, respectively. Secretome-treated mice also had greater whole-body physical function (grip strength and rotarod performance) and had higher energy expenditure and physical activity levels compared to control mice. Furthermore, secretome-treated mice had greater skeletal muscle Pax7+ cell abundance, capillary density, collagen IV turnover, reduced intramuscular lipids, and greater Akt and hormone sensitive lipase phosphorylation in adipose tissue. Finally, secretome treatment in vitro directly enhanced muscle cell growth and IL-6 production, and in adipocytes, it reduced lipid content and improved insulin sensitivity. Moreover, indirect treatment with secretome-treated myotube culture media also enhanced muscle cell growth and adipocyte size reduction.

Together, these data suggest that intramuscular treatment with a stem cell secretome improves whole-body metabolism, physical function, and remodels skeletal muscle and adipose tissue in aged mice.

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A View of Type 2 Diabetes as Accelerated Aging

The mortality characteristics resulting from type 2 diabetes look very much like an accelerated form of normal aging, as noted in today's open access paper reporting on a large epidemiological study. This mortality characteristic is so much like aging that at times in the past researchers have used animal models of type 2 diabetes as stand-ins for aging, in order to conduct studies more rapidly. Type 2 diabetes is a metabolic disease, a condition that usually arises from excess fat tissue, and is characterized by chronic inflammation, excessive blood sugar, high levels of circulating advanced glycation end-products, and other disruptive influences resulting from too much fat in the body, a state of hyperlipidemia.

In some senses being overweight is a form of accelerated aging: it results in a greater burden of senescent cells, for example. Mammals have evolved the capacity to become fat, but not to operate well over the long term while being fat. Perhaps the most important thing to note about type 2 diabetes is that it is reversible even in its late stages; type 2 diabetes is in a sense actively maintained by the presence of excess fat tissue. Sustained low calorie diets and weight loss have been shown to profoundly reverse type 2 diabetes in human clinical trials.

Mortality of type 2 diabetes in Germany: additional insights from Gompertz models

The Gompertz law of mortality proclaims that human mortality rates in middle to old ages grow log-linearly with age and this law has been confirmed at multiple instances. We investigated if diabetes mortality in Germany also obeys the Gompertz law and how this information helps to communicate diabetes mortality more intuitively.

We analyzed all statutory health-insured persons in Germany in 2013 that were aged 30 years or older. Deaths in 2014 were recorded and given in 5-year age groups. The study population consisted of 47,365,120 individuals, 6,541,181 of them with diabetes. In 2014, 763,228 deaths were recorded, among them 288,515 with diabetes. We fitted weighted linear regression models (separately for females and males and for people with and without diabetes) and additionally computed the probability that a person with diabetes dies before a person of the same age and sex without diabetes, and the "diabetes age", that is, the additional years of mortality risk added to an individual's chronological age due to diabetes-related excess mortality.

We found that diabetes mortality for females and males aged 30 years or older in Germany in 2014 followed the Gompertz law of mortality. The survival information of the population with diabetes during a large part of the lifespan can thus be reduced to the two parameters of the Gompertz distribution. In addition, the Gompertz distribution gives better fits than two competing, mechanistically also plausible distributions for the age at death. The probability that a female/male with diabetes dies before a female/male without diabetes (and the same age) is 61.9%/63.3%.

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Raised Inflammatory Markers Somewhat Correlate with Incidence of Age-Related Disease

Onset, progression, and resolution of inflammation are all driven by the interaction of many different complex signaling processes. The immune system as a whole is highly complex, an array of many different interacting populations of specialized cells. Nonetheless, there are a few individual circulating signal proteins that, to some degree at least, tend to reflect overall inflammatory status. Not reliably, but enough to produce correlations in patient populations of any reasonable size.

Today's open access paper is a survey of the literature on inflammatory cytokines IL-6, TNF, and IL-1β, pulling reported measures and patient comorbidities from many different published studies. As one might expect, there is a correlation between raised levels of inflammatory cytokines and the presence of age-related disease. Chronic inflammation is a feature of aging, and it is known to accelerate the progression of all of the common age-related conditions. The correlation isn't large or strong, however, indicating the point made above: individual cytokines are not great measures of the state of the immune system, and what they do in fact reflect varies widely from individual to individual. The state of chronic, unresolved inflammation is too complex to be measured so simply.

Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis

Aging facilitates a pro-inflammatory state by disrupting the peripheral immune system, which leads to excessive innate immune activity with the release of pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines. Different pro-inflammatory cytokines, such as interleukins: IL-1β, IL-6, IL-12, IL-18, interferon (IFN-γ), and tumor necrosis factor (TNF), as well as anti-inflammatory ones, such as IL-4, IL-10, IL-13, and IL-19 which are secreted from immune cells, interact with body cells to mediate the immune responses and thus elicit its most optimum outcome.

Elevated levels of interleukin-6 and TNF, as well as IL-1β, are associated with diseases, disability, and mortality in older adults. Interleukin-6, also known as 'the cytokine for gerontologists', plays a key role in the acute phase response in metabolic control and in the pathogenesis of many chronic diseases. IL-6 is produced mainly by the monocytes and macrophages. It produces a pleiotropic effect, and although in healthy and younger people its level is usually relatively low, in the elderly its elevated levels may correlate with increased mortality. IL-1β is produced in large quantities during infections and other stressful events. High glucose concentration was reported to stimulate the production of IL-1β by pancreatic β cells, which implies the role of this cytokine also in type 2 diabetes. TNF is a pro-inflammatory mediator that can produce beneficial effects when activated locally in the tissues but it can be highly harmful when released systemically. It is one of the most important cytokines, produced by several types of cells: monocytes, T-cells, macrophages, fibroblast, adipocytes, and smooth muscle cells. In elderly people and centenarians, it has been shown that the level of TNF rises, which significantly increases mortality.

The assessment of chronic inflammation, including the level of pro-inflammatory cytokines in elderly people with comorbidities, may be the key to more effective treatment. Our hypothesis was that independent measurements of cytokines such as IL-6, TNF and IL-1β were significantly associated with the development of age-related diseases. Therefore, the aim of this study was to independently evaluate three cytokines: IL-6, TNF and IL-1β in elderly people with comorbidities compared to disease-free controls.

The electronic bibliographic PubMed database was systematically searched to select all the relevant studies published up to July 2023. The total number of the subjects involved in the meta-analysis included patients with diseases (n = 8,154) and controls (n = 33,967). The overall concentration of IL-6 was found to be higher in patients with diseases compared to controls and the difference was statistically significant. The heterogeneity was considerable. The potential diagnostic usefulness of IL-6 was confirmed by odds ratio (OR) analysis, with OR = 1.03. The concentration of both TNF and IL-1β was elevated in the control group compared to patients. For TNF, however, the difference was statistically insignificant.

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A Survey of MicroRNAs Shown to be Relevant to Muscle Aging

RNA molecules are produced in the cell nucleus by transcription machinery that reads gene sequences from the genome. MicroRNAs are among the varieties of RNA molecule that are not translated by a ribosome to produce proteins. Instead they directly participate in cell functions, often by altering the expression of other genes. Many microRNAs appear to be important players in the regulation of specific cell behaviors and tissue functions, such as regeneration and maintenance of tissues.

In today's open access paper, the authors provide an overview of some of the microRNAs that have been identified as important or potentially interesting in the context of the aging of muscle tissue, particularly in the decline of maintenance and regeneration. In the broader context beyond muscle tissue, a few first therapies that target specific microRNAs are making their way towards the clinic, primarily to treat forms of cancer. A broader range of such therapies is a possibility for the years ahead, including those aimed at restored muscle function in later life.

The role of non-coding RNAs in muscle aging: regulatory mechanisms and therapeutic potential

Non-coding RNAs (ncRNAs) are a varied family of RNA that do not code for proteins but are crucial for many biological activities, including gene regulation, epigenetic modifications, and chromatin remodeling. This class of RNAs includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and others. Non-coding RNAs have emerged as critical players in the regulation of various cellular processes, including those governing muscle tissue. In the context of muscle aging, research has uncovered a wealth of information about the roles ncRNAs play in mediating muscle loss, muscle regeneration, and overall muscle maintenance. For instance, modulating these miRNAs, such as miR-29, miR-143, and miR-431, could potentially improve age-related muscle regeneration.

In 2016, miR-501-3p was identified as a muscle-specific miRNA enriched in activated myogenic progenitor cells during muscle regeneration. Subsequent research demonstrated that miR-501 knockout mice exhibited a significant reduction in the diameter of newly formed myofibers. This result is a result of miR-501 controlling the expression of the sarcomeric gene via the estrogen-related receptor gamma (Esrrg). Another noteworthy miRNA, miR-7a-1, has been identified as highly expressed in aged muscle and as a downstream factor of HuR and Msi2. This miRNA plays a role in inhibiting the translation of Cry2 and modulating Muscle Stem cell (MuSC) differentiation. These findings contribute to our understanding of how miRNAs are involved in muscle regeneration and the aging process.

Some miRNAs, known as senescence-associated miRNAs, are identified that differentially expressed during cellular senescence contribute to its establishment and maintenance. For instance, miR-24 has been found to be downregulated in ex vivo MuSCs and regenerating muscle during aging. miR-24 regulates the generation of mitochondrial ROS through Prxd6 and subsequently influences MuSCs viability, myogenic potential and senescence. Modulating miR-24 in aged mouse are preserve satellite cells viability and mitochondria function.

Sarcopenia, characterized by age-related muscle loss, is influenced by various factors, with increased expression of E3 ligases like MuRF1 and Atrogin-1 in aged muscles, highlighting their involvement in the ubiquitin-proteasome system. Recent research has identified specific miRNAs associated with sarcopenia that target or modulate these E3 ligases, underscoring their importance in maintaining muscle. Notably, miRNAs located within the Dlk1-Dio3 cluster have induced hypertrophic phenotypes in myotubes. Among these miRNAs, including miR-376c, miR-668, miR-1197, miR-495, miR-377, miR-379, and miR-431, they directly bind to the 3′UTR of Atrogin-1, leading to the suppression of Atrogin-1 in both human and mouse muscle cells. Furthermore, miR-376c has shown remarkable potential in ameliorating skeletal muscle atrophy and improving muscle function in old mice. These miRNAs consistently exhibit downregulation in aged human muscles.

Recent studies have reported on the regulation of mitochondrial homeostasis controlling muscle mass. It was shown that miR-181a is crucial in controlling the age-related alteration of mitochondrial dynamics in muscle via targeting p62 and Park2. In vivo restoration of miR-181a levels in the muscles of old mice inhibited the accumulation of p62, Park2, and DJ-1 while maintaining mitochondrial content. In the end, this enhanced the size and force of myofibers. Collectively, these results indicate that miR-181a functions as an effective mitochondrial dynamics regulator, both in vitro and in vivo.

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Naked Mole Rats are Resistant to Ischemia, Such as Occurs Following a Heart Attack

On the one hand, naked mole-rats are most likely long-lived because they live underground, and thus suffer much lower rates of predation than other similarly sized mammals. Lower rates of extrinsic mortality appear to be a necessary prerequisite for the evolution of a longer species life span. On the other hand, living in a low-oxygen environment appears to have spurred the evolution of broad range of adaptations to that environment that incidentally happen to extend species longevity. Today's open access paper covers one aspect of those adaptations, a resistance to ischemia that reduces the harms resulting from the loss of blood flow to important tissues that takes place during events such as a heart attack.

Interestingly, the researchers note differences in tolerance to hypoxia between naked mole-rats and similar species that correlate with a greater exposure to the low-oxygen underground environment. One can imagine interactions over evolutionary time between the characteristics of predation, instinct and willingness to remain underground, tolerance to hypoxia, and life span. Does all this discovery have relevance to human medicine? That remains an open question. Certainly there is considerable enthusiasm for understanding exactly how naked mole-rats are near immune to cancer, and building therapies based upon that understanding. It remains to be seen as to whether this is a practical goal, however.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

While data on O2/CO2 levels in wild naked mole-rat (NMR) burrows is limited and has never been measured in a nest chamber full of animals, NMRs in captive colonies are able to tolerate hours of extreme hypoxia (5% O2 for up to 300 minutes), and can even survive up to 18 minutes of anoxia. NMRs often elect to spend more time in areas of their burrow system with extreme atmospheric conditions including the nest chamber, where they may spend up to 70% of their time. This is something not regularly seen in other social African mole-rat species.

This challenging hypoxic habitat creates strong selective pressures and has driven the evolution of unique adaptive traits in NMRs. Mammalian cells are not usually hypoxia-resistant, requiring uninterrupted O2 availability for survival. Fluctuations in O2 availability can lead to ischaemia/reperfusion injury and irreversible organ damage such as is observed following a heart attack. Given the absence of cardiovascular disease in NMRs, despite regular fluctuating exposure to hypoxia/anoxia and normoxia, NMR hearts appear to have evolved resistance to both reduced O2 availability and ischaemia/reperfusion (I/R) injury.

NMR metabolism has unusual features, such as the ability to switch from glucose to fructose-driven glycolysis in the brain during anoxia. However, the mechanisms that underpin the extraordinary physiological adaptation to limited O2 availability in the heart are unknown. To determine how these adaptations arise in NMR, we hypothesised that comparison to other African mole-rat genera would enable us to infer the changes in gene expression and metabolic signatures that contribute to the extreme hypoxia tolerance, resistance to cardiovascular injury, and longevity of NMRs.

To identify the mechanisms behind these exceptional traits, metabolomics, and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57BL/6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57BL/6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

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Reversal of Markers of Aging in Cells Following Small Molecule Partial Reprogramming

Partial reprogramming by exposure to Yamanaka factors resets many of the epigenetic changes characteristic of cells in aged tissue. This is a potential approach to the production of future rejuvenation therapies. At present, some research groups are attempting to move away from genetic interventions to find small molecules that can provoke reprogramming. There are some avenues that seem promising. Here, researchers assess the effects of partial reprogramming by small molecules on a range of omics data and functional parameters for cells, finding that the outcomes are much as one would expect for a successful protocol.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear.

Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites.

Using both transcriptomic clock and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

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Efferocytosis in the Context of Aging and Age-Related Disease

There is something of a tradition in the aging research community of writing reviews that attempt to summarize everything that is known of a single specific cellular behavior in the context of the panoply of cell and tissue dysfunction observed in aging. Today it is the turn of efferocytosis, the clearance of dying cells and their immediate debris by phagocytes such as macrophages of the innate immune system. It is fairly straightforward to mount an argument to suggest that more efficient efferocytosis is a good thing, as unwanted consequences attend the presence of lingering cell corpses cluttering up tissue. Like autophagy, the mechanisms making up efferocytosis are fairly well mapped, but unlike autophagy, there is no great effort underway in the research community to find ways to improve efferocytosis for functional benefit.

Efferocytosis is carried out by professional phagocytes, such as macrophages, dendritic cells, and other nonprofessional cells, to engulf apoptotic cells (ACs). Initially, phagocytes expeditiously and securely eliminate the membrane structure of the dying cell before its disintegration and subsequent release into adjacent tissue. This process serves to safeguard the surrounding tissue against the deleterious effects induced by toxic enzymes, oxidants, and intracellular components, such as protease antibodies and caspases within ACs. Additionally, efferocytosis can generate a significant number of biological factors, including vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which are hypothesized to facilitate cellular regeneration within the body. In addition, efferocytosis elicits subsequent intracellular signalling cascades, including anti-inflammatory, anti-protease, and growth-promoting actions.

The coordination of many processes is essential for the proper differentiation of ACs from healthy cells and their subsequent elimination through efferocytosis. When these deceased cells remain uninterrupted, they undergo a disruptive process, resulting in harm to the organism, triggering an inflammatory reaction, and perhaps giving rise to a range of ailments. Numerous human diseases, such as atherosclerosis, cancer, systemic lupus erythematosus, diabetes, obesity, rheumatoid arthritis, and aging, have been observed to exhibit associations with deficiencies or alterations in the processes of efferocytosis. Efferocytosis is a multistep physiological process and enhancing any one of these steps can promote efferocytosis while suppressing tissue inflammation.

Hence, the concurrent implementation of strategies aimed at augmenting efferocytic mechanisms and anti-aging treatments has the potential to serve as a potent intervention for extending the duration of a healthy lifespan. In this review, we comprehensively discuss the concept and physiological effects of efferocytosis. Subsequently, we investigated the association between efferocytosis and the hallmarks of aging. Finally, we discuss growing evidence regarding therapeutic interventions for age-related disorders, focusing on the physiological processes of aging and efferocytosis.

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Lewy Body Disease May Be More Common than Thought

Access to human brain tissue for medical research is more limited than most people realize is the case, and, for obvious reasons, far too little of the available tissue data covers the early stages of disease. This limitation is one of the factors slowing the pace of research into age-related neurodegenerative conditions. Here, for example, researchers make use of an unusual resource to show that the prevalence of Lewy body disease may be greater than presently thought, with pathology beginning in the 50s, even if there are no outright symptoms of disease at that stage.

Lewy body disease is the second most common brain degenerative disease after Alzheimer's disease. Lewy bodies, deposits of alpha-synuclein protein, are found in the brainstem, limbic system, and cerebral cortex. Similar tissue changes are also seen in patients clinically diagnosed with Parkinson's disease. Lewy body disease can be difficult to recognise at the beginning of the disease, as it progresses slowly. Symptoms often include movement disturbances, memory problems, and psychiatric symptoms.

In their recent study, researchers investigated for the first time the occurrence of Lewy body disease markers in young and middle-aged subjects who were not known to suffer from Lewy body or Parkinson's diseases. In their study, the researchers used unique Finnish forensic autopsy data, which consists of approximately 600 people aged 16-95 who died outside hospitals. Previous similar studies have investigated the occurrence of the disease markers in people over 60 years old. The researchers found that Lewy body disease changes may begin to develop in the brain already in middle age, even if there are no actual symptoms yet.

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Chronic Pain Accelerates Brain Aging, Perhaps via Inflammation

A range of conditions produce chronic pain in muscle and skeletal tissue. While conditions such as osteoathritis are comparatively well understood, the etiology of chronic muscular pain disorders such as myofascial pain syndrome is poorly understood and treatment options are consequently limited. Here, researchers analyze available epidemiological data on knee osteoarthritis, and show that it suggests an inflammatory link between chronic pain and an accelerated pace of degenerative brain aging.

Individuals suffering from chronic musculoskeletal pain (CMP) may face a higher high risk of brain aging. CMP is a leading cause of disability, affecting more than 40% of the world's population and impacting patients' cognitive function. Although the exact mechanism is not fully understood, thus hampering prevention and treatment efforts, research indicates that inflammatory markers associated with brain aging are higher in CMP patients, suggesting a link between brain aging and CMP.

Using structural MRI data from over 9,000 individuals, researchers developed a brain age model to compare brain age to chronological age. They found that individuals with knee osteoarthritis, who were identified from both the UK Biobank and additional replication datasets from the local community, experienced more rapid brain aging than healthy individuals. In addition, brain regions responsible for human cognitive function, such as the hippocampus, were found to be associated with such accelerated brain aging.

Moreover, the researchers delved into the genetic landscape and identified the gene SLC39A8 as a shared link between knee osteoarthritis and accelerated brain aging. This gene, which is particularly expressed in microglial cells and astrocytes, underscores the potential role of inflammation and neurodevelopment in the observed phenomena.

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Arguing the Primacy of Predation in Determining Species Longevity

Researchers here review a variety of species and conclude that defense against predation is the most important determinant of species longevity. Long-lived species tend to have shells, or fly, or live underground. Evolution will not favor longevity until other factors reduce extrinsic mortality at the hands of predators. After that, proximate biochemical causes of longevity can come into play in what looks to be a wide variety of ways.

Various environmental morphological and behavioral factors can determine the longevity of representatives of various taxa. Long-lived species develop systems aimed at increasing organism stability, defense, and, ultimately, lifespan. Long-lived species to a different extent manifest the factors favoring longevity, such as body size, slow metabolism, activity of body's repair and antioxidant defense systems, resistance to toxic substances and tumorigenesis, and presence of neotenic features.

In continuation of our studies of mammals, we investigated the characteristics that distinguish long-lived ectotherms (crocodiles and turtles) and compared them with those of other ectotherms (squamates and amphibians) and endotherms (birds and mammals). We also discussed mathematical indicators used to assess the predisposition to longevity in different species, including standard indicators (mortality rate, maximum lifespan, coefficient of variation of lifespan) and their derivatives. Evolutionary patterns of aging are further explained by the protective phenotypes and life history strategies.

We assessed the relationship between the lifespan and various studied factors, such as body size and temperature, encephalization, protection of occupied ecological niches, presence of protective structures (for example, shells and osteoderms), and environmental temperature, and the influence of these factors on the variation of the lifespan as a statistical parameter. Our studies did not confirm the hypothesis on the metabolism level and temperature as the most decisive factors of longevity. It was found that animals protected by shells (e.g., turtles with their exceptional longevity) live longer than species that have poison or lack such protective adaptations. The improvement of defense against external threats in long-lived ectotherms is consistent with the characteristics of long-lived endotherms (for example, naked mole-rats that live in underground tunnels, or bats and birds, whose ability to fly is one of the best defense mechanisms).

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Reversing Myeloid Bias by Selective Destruction of Hematopoietic Cells

The hematopoietic cell populations of the bone marrow are responsible for producing red blood cells and immune cells. With advancing age, the production of immune cells shifts to bias myeloid cells of the innate immune system versus lymphocyte cells of the adaptive immune system. This is thought to be an important aspect of immune aging. Researchers here attempt to reverse this myeloid bias in immune cell production by selectively destroying some of the myeloid-focused hematopoietic cells, an interesting idea. The results are positive and intriguing.

During aging, the number of hematopoietic stem cells (HSCs) that make balanced proportions of lymphocytes and myeloid cells decline, while those that are myeloid-biased increase their numbers. This favors the production of myeloid cells. Early in human history, when people rarely left their birthplace and lived shorter lives, this gradual change probably had no consequences (it may even have been favorable) because people were likely to encounter all their surrounding pathogens by young adulthood and be protected by their memory lymphocytes. But now it's distinctly disadvantageous.

The researchers wondered if they could tilt the balance back toward a younger immune system by depleting myeloid-leaning HSCs and allowing the more balanced HSCs to replace them. Their hunch was correct. Mice between 18 and 24 months old (doddering in the mouse world) that were treated with an antibody targeting the myeloid-leaning HSCs for destruction had more of the balanced HSCs - and more new, naïve B lymphocytes and naïve T lymphocytes - than their untreated peers even several weeks later.

"These new, naïve lymphocytes provide better immune coverage for novel infections like those humans increasingly encounter as our world becomes more global. Without this renewal, these new infectious agents would not be recognized by the existing pool of memory lymphocytes. Not only did we see a shift toward cells involved in adaptive immunity, but we also observed a dampening in the levels of inflammatory proteins in the treated animals. We were surprised that a single course of treatment had such a long-lasting effect. The difference between the treated and untreated animals remained dramatic even two months later."

When the treated animals were vaccinated eight weeks later against a virus they hadn't encountered before, their immune systems responded more vigorously than was the case for the untreated animals, and they were significantly better able to resist infection by that virus. Finally, the researchers showed that mouse and human myeloid-biased HSCs are similar enough that it may one day be possible to use a similar technique to revitalize aging human immune systems, perhaps making a person less vulnerable to novel infections and improving their response to vaccination.

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Dephosphorylation-Targeting Chimeras to Clear Tau Aggregates in Alzheimer's Disease

Researchers here describe an interesting evolution of proteolysis targeting chimera (PROTAC) technology into a form that upregulates the dephosphorylation of tau protein. Tau becomes pathogenic in the aging brain when hyperphosphorylated, and thus reducing it back to its unphosphorylated form should provide benefits to patients in tauopathies such as Alzheimer's disease. The PROTAC style of approach, when applied to this situation, is to produce a molecule capable of binding to phosphorylated tau at one end and a phosphatase at the other. By encouraging phosphatase molecules into close proximity to phosphorylated tau, the pace at which dephosphylation occurs is greatly upregulated.

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. Following the development of proteolysis targeting chimeras (PROTACs) for selectively strengthening degradation of protein of interest (POI), a variety of new chimeras, like autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTEC), lysosome-targeting chimeras (LYTACs), antibody-based PROTACs (AbTACs) or proteolysis-targeting antibodies (PROTABs), have been developed. Taking advantage of these technologies, we and others have developed several chimeras for selectively facilitating tau removal in AD and other tauopathies.

Notwithstanding, the general removal of tau protein might be somewhat arbitrary since tau per se plays multifaceted physiological roles in maintaining cell structure and functions. It is the pathological hyperphosphorylation of tau that initiates the formation of neurofibrillary tangles and neurodegeneration in tauopathies. Therefore, specific downregulation of tau phosphorylation might be more refined for the therapy of these diseases. However, direct use of either tau kinase inhibitors or phosphatase activators should take unacceptable toxic side effects, because each of these enzymes acts to concurrently modulate the numerous signaling pathways aside from tau.

To achieve better selectivity and inspired by the design of PROTAC-like chimeras, we have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specific suppression of tau hyperphosphorylation. Our DEPTAC consists of the following motifs: (1) a "warhead" specifically recognizing and binding tau (named tau binder, TB), (2) an "anchor" for recruiting phosphatase (named phosphatase recruiter, PPR), (3) an inter-motifs linker, (4) a cell membrane-penetrating sequence, if necessary. Here, we reported the generation and screening principle of DEPTACs and the further verification of their therapeutic effectiveness in cell and animal models of tauopathy.

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Using mRNA to Generate Therapeutic Antibodies in the Brain

It may turn out to be cost-effective to replace delivery of therapeutic monoclonal antibodies with delivery of messenger RNA (mRNA), encapsulated in a lipid nanoparticle or linked to a cell penetrating molecule of some sort in order to reach the desired tissues and be taken up into the cytoplasm. Researchers here consider this in the context of treating Alzheimer's disease, where the primary thrust of therapeutic development involves the use of antibodies targeting the various protein aggregates thought to contribute to disease progression.

Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer's disease. In the last year, two anti-amyloid monoclonal antibodies, lecanemab and aducanumab, have been approved in the USA for the treatment of Alzheimer's disease, whilst several tau-targeting monoclonal antibodies are currently in clinical trials. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects.

Synthetic in vitro-transcribed mRNA encoding antibodies for endogenous protein expression holds the potential to overcome many of the limitations associated with protein antibody production. Here, we have generated synthetic in vitro-transcribed mRNA encoding a tau specific antibody as a full-sized immunoglobulin and as a single-chain variable fragment. In vitro transfection of human neuroblastoma SH-SY5Y cells demonstrated the ability of the synthetic mRNA to be translated into a functional tau-specific antibody. Furthermore, we show that the translation of the tau-specific single-chain variable fragment as an intrabody results in the specific engagement of intracellular tau.

This work highlights the utility of mRNA for the delivery of antibody therapeutics, including intrabodies, for the targeting of tau in Alzheimer's disease and other tauopathies.

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Transient Pockets of Hypoxia in the Mammalian Brain

Evidence suggests that the mammalian brain is operating at the very edge of its capacity, supplied with just enough oxygen and nutrients to barely get by. That exercise produces measurable short-term gains in cognitive function, while blood flow is increased, is one point in favor of this view. Another is provided here, in which researchers note that it is entirely normal to observe transient areas of hypoxia in the brain at rest, and that the occurrence of these regions is diminished by the increased blood flow of exercise. It is an open question as to what to do with this finding: we can imagine future technologies that greatly increase the capacity of the blood to carry oxygen around the body, but equally it is also the case that mild hypoxia is actually beneficial. A little stress provokes better cell maintenance.

Using a bioluminescent oxygen indicator, researchers discovered a spontaneous, spatially defined occurrence of "hypoxic pockets" in the mouse brain. Their technique offers a way to learn more about brain oxygen tension (pO2), a measure of oxygen delivery and demand in brain tissue that changes dynamically but is not well understood. The findings could have implications for how rest and exercise affect pO2 in the human brain, including the role of these activities in conditions such as dementia.

The researchers used a genetically encoded bioluminescent oxygen indicator in mouse cortical astrocytes to track pO2 changes. Under resting conditions, pO2 changed often and included transient but sharply defined events of hypoxia that lasted several seconds to minutes and were spatially confined. Further research confirmed that the hypoxic pockets were caused by circulation changes in the brain's capillaries. During exercise, the area covered by hypoxic pockets in the mouse brain decreased by 52% compared to the brain during rest.

"Our study predicts that physical inactivity has direct effects on tissue pO2 by favoring capillary occlusions and increasing the number of hypoxic pockets. Conversely, simply increasing sensory input or locomotion rapidly suppress the occurrence of hypoxic pockets perhaps explaining the linkage between sedentary lifestyle and an increased risk of dementia." As pO2 decreases with age, the researchers also note that their technique might someday be used to determine if hypoxic pockets expand or last longer with age.

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Skin Biopsy as an Approach to Diagnose Parkinson's Disease

Researchers here demonstrate that the presence of phosphorylated α-synuclein in a skin biopsy is a good indicator of the presence of Parkinson's disease and other synucleinopathies. A skin biopsy is a more invasive procedure than most people want to undergo, but a greater ability to diagnose progressive diseases in their early stages will nonetheless tend to encourage the development of a greater ability to manage, treat, and avoid the later stages.

Affecting an estimated 2.5 million people in the United States, the synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). While the four progressive neurodegenerative diseases have varying prognoses and do not respond to the same therapies, they do share some overlapping clinical features such as tremors and cognitive changes. Additionally, all are characterized by the presence of an abnormal protein present in the nerve fibers in the skin called phosphorylated α-synuclein (P-SYN).

In this investigation, titled the Synuclein-One Study, researchers enrolled 428 people, ages 40-99 years, with a clinical diagnosis of one of the four synucleinopathies based on clinical criteria and confirmed by an expert panel or were healthy control subjects with no history of neurodegenerative disease. Participants underwent three 3-millimeter skin punch biopsies taken from the neck, the knee, and the ankle.

Among the participants with clinically confirmed PD, 93 percent demonstrated a positive skin biopsy for P-SYN. Participants with DLB and MSA tested 96 percent and 98 percent positive, respectively. One hundred percent of participants with PAF were positive for the abnormal protein. Among the controls, just over 3 percent tested positive for P-SYN - an error rate the authors suspect may indicate some of the healthy controls are at risk for a synucleinopathy. "Parkinson's disease and its subgroup of progressive neurodegenerative diseases show gradual progression, but alpha-synuclein is present in the skin even at the earliest stages."

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