Fight Aging!

One of the reasons why older people exhibit chronic inflammation is that innate immune pathways such as that involving the STING protein react inappropriately to signs of age-related molecular damage in the cell, such as mislocalized mitochondrial DNA. Thus some research has aimed at producing ways to inhibit STING activity. A big issue with all such suppression of inflammatory regulators is that the normal, necessary inflammation required for defense against pathogens and coordination of regeneration makes use of the same pathways. No-one has yet found a way to suppress only unwanted inflammation by targeting regulators of inflammation. The only way forward appears to be to remove the triggers of inflammation, a task that remains a sizable challenge for most of those triggers.

Here, researchers find another blocking issue specific to STING, which is that in addition to promoting inflammation the protein also acts to improve autophagy via increased creation of lysosomes. Autophagy is a complex cell maintenance process that delivers surplus and damaged proteins and structures to a lysosome for disassembly into raw materials for further protein synthesis. It is well demonstrated that improved autophagy modestly slows aging, even if specifically achieved by only improving lysosomal function. Suppressing STING would therefore impair autophagy and modestly accelerate aging, likely ruling this out as a strategy for reducing age-related chronic inflammation.

Double-edged STING: study identifies new pathway involved in aging

In healthy human cells, DNA is packaged up inside the nucleus and mitochondria. When DNA leaks out into the fluid component of the cell known as the cytosol, it means that something is wrong. Cytosolic DNA is a danger signal associated with infections, cellular stress, cancer, and other diseases. Cells have a warning system to detect DNA in the cytosol, which involves activation of STING, which in turn coordinates inflammation necessary to combat these threats. While short bursts of STING-mediated inflammation are crucial, in some people this pathway is chronically "on," a state that has been linked with neurodegeneration and other diseases of aging, as well as normal aging.

To learn more about potential benefits of STING activation in response to diverse stresses, researchers analyzed the full set of proteins within cells. They found that when STING was activated, two transcription factors called TFEB and TFE3 were shuttled to the nucleus of cells, where they activated genes that resulted in the production of more lysosomes. Lysosomes are organelles that are involved in autophagy, a cellular process that cleans up damaged material, almost like a housekeeping or recycling system. Both lysosomes and autophagy are tightly linked with longevity and healthspan, the length of time that a person is healthy, suggesting that this protective function of STING is important for healthy aging.

STING-blocking therapies are currently being explored within the context of age-related diseases, but the new findings suggest that this strategy should be reconsidered because it would also block the autophagy/lysosome-promoting functions of STING. Instead, selectively targeting components of the inflammation pathway downstream of STING may be a better approach because it would preserve the protein's beneficial functions.

A TBK1-independent primordial function of STING in lysosomal biogenesis

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING.

Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.

Cellular metabolism is highly complex, but that complexity can be divided into functional modules that only interact with one another indirectly. Those indirect interactions do exist, however, and so loss of function in one module will tend to affect others. In this way aging is a process of countless distinct changes, but the effects of those changes are felt everywhere. Or so we might hypothesis, analogously to our experience that declining function in one organ (the kidney, say) will have negative effects on the function of all of the other organs in the body. That said, should we should expect aging to occur uniformly across distinct functional areas of cell biochemistry? Researchers here present data in support of the idea that the progression of aging is not uniform at all when considered at this level.

The aging process involves numerous molecular changes that lead to functional decline and increased disease and mortality risk. While epigenetic aging clocks have shown accuracy in predicting biological age, they typically provide single estimates for the samples and lack mechanistic insights. In this study, we challenge the paradigm that aging can be sufficiently described with a single biological age estimate. We describe Ageome, a computational framework for measuring the epigenetic age of thousands of molecular pathways simultaneously in mice and humans.

Ageome is based on the premise that an organism's overall biological age can be approximated by the collective ages of its functional modules, which may age at different rates and have different biological ages. We show that, unlike conventional clocks, Ageome provides a high-dimensional representation of biological aging across cellular functions, enabling comprehensive assessment of aging dynamics within an individual, in a population, and across species. Application of Ageome to longevity intervention models revealed distinct patterns of pathway-specific age deceleration. Notably, cell reprogramming, while rejuvenating cells, also accelerated aging of some functional modules. When applied to human cohorts, Ageome demonstrated heterogeneity in predictive power for mortality risk, and some modules showed better performance in predicting the onset of age-related diseases, especially cancer, compared to existing clocks.

Together, the Ageome framework offers a comprehensive and interpretable approach for assessing aging, providing insights into mechanisms and targets for intervention.

Link: https://doi.org/10.1101/2024.09.17.613599

Researchers here report on initial in vitro studies of a novel approach to improve mitochondrial function via an increased pace of mitochondrial replication. It is typically a long road from positive results in cell culture to a viable basis for therapy, and most cell work proves to be less useful than hoped in animals, but the novelty of the approach here makes it interesting. It is certainly true that new and better ways to improve mitochondrial function in aged tissues are much needed. It is an open question as to whether a compensatory approach based on increased mitochondrial replication will be usefully beneficial in the age-damaged environment in which the function of each individual mitochondrion is degraded.

Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function.

In this study, we designed molybdenum disulfide (MoS2) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS2 nanosheets. Treatment of mammalian cells with MoS2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types.

Taken together, this study reveals that predefined atomic vacancies in MoS2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis.

Link: https://doi.org/10.1038/s41467-024-52276-8

The primary function of the APOE protein is lipid transport, appearing in many of the different forms of cholesterol transport particles. Like all proteins in the body APOE is involved in more processes than just its primary function. There are a number of common variants of the APOE gene, all slightly altering the behavior of the protein. The APOEε4 variant is notable because it significantly increases the risk of suffering Alzheimer's disease; in other words it accelerates age-related neurodegeneration.

In recent years, evidence has pointed to the effects of APOEε4 on the innate immune cells known as microglia, found in the brain but not the rest of the body. APOEε4 makes microglia more inflammatory, and increased microglial inflammation is strongly implicated in brain aging. Microglia are the central nervous system version of the innate immune cells called macrophages found everywhere else in the body. Macrophages in tissues very close to the brain, such as the choroid plexus, are known as border-associated macrophages and their inflammatory behavior is also implicated in the progression of neurodegenerative conditions.

Interestingly, the authors of today's open access paper report that APOEε4 is disruptive to the behavior of border-associated macrophages. They focus on the generation of oxidative stress by macrophages rather than inflammation, but it is worth noting that inflammation and oxidative stress usually go hand in hand in aged tissues.

A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury

Microvascular damage to the subcortical white matter is a major contributor to age-related dementia, including Alzheimer's disease (AD). Supplied by terminal arterioles with limited collateral flow from adjacent vascular territories, the subcortical white matter is particularly vulnerable to microvascular injury. Although vascular risk factors, such as hypertension and diabetes, are strongly linked to white matter lesions, accumulating evidence indicates that ApoE4, the leading genetic risk factor in sporadic AD, also increases the risk for cognitive impairment produced by vascular factors. Thus, ApoE4 carriers exhibit vascular pathology, microvascular alterations, and more white matter lesions linked to cognitive impairment.

ApoE4 is well known to be associated with alterations of the neurovasculature. ApoE4-positive individuals have dysregulated cerebral blood flow (CBF), as well as increased permeability of the blood-brain barrier (BBB) in the setting of AD. However, the cellular sources of ApoE4, the effector cells in the cerebral microvasculature and the signaling mechanisms driving the dysfunction remain unclear.

Although microglial cells reside in the brain parenchyma, border-associated macrophages (BAMs) seed the meninges, the choroid plexus and the space surrounding microvessels as they dive into the brain (perivascular space). BAMs are enriched with free radical-producing enzymes and, owing to their proximity to pial arterioles in the leptomeninges and to penetrating arterioles in the perivascular space, have recently emerged as a major cause of neurovascular dysfunction in animal models of neurodegeneration.

In the present study, we investigated the sources and targets of ApoE responsible for neurovascular dysfunction and the mechanisms of the effect. We found that ApoE4 acts on BAMs to alter critical cerebrovascular regulatory mechanisms through NADPH oxidase (NOX)-dependent production of reactive oxygen species (ROS). The dysfunction is abolished by BAM depletion or by genetic deletion of ApoE4 selectively in BAMs, identifying these cells as the sole source of the ApoE4 mediating the deleterious vascular effects.

Using a bone marrow (BM) transplantation strategy, we found that ApoE4-positive BAMs induce neurovascular dysfunction in ApoE3-TR mice, whereas ApoE3-positive BAMs rescue neurovascular dysfunction in ApoE4-TR mice, indicating that BAMs are also the main effectors of the dysfunction. Attesting to the pathogenic effect of BAM ApoE4 on white matter injury, ApoE4-positive BAMs enhance white matter damage and cognitive impairment in ApoE3-TR mice, whereas ApoE3-positive BAMs rescue this phenotype in ApoE4-TR mice. The findings establish BAMs as both sources and effectors of the ApoE4 acting on the cerebral microvasculature, unveiling a previously unappreciated cell-autonomous role of brain-resident macrophages in the neurovascular dysfunction and propensity of white matter injury associated with ApoE4.

A good tissue model tends to speed up research to the degree that it is less costly and easier to manage than animal models. This is especially true of age-related conditions, as the animal models tend to require a supply of aged animals, which is relatively expensive in terms of time and cost when compared with maintaining a supply of young animals. It is a little early to say whether the model of wrinkle formation noted here is a good tissue model, whether it adequately replicates the mechanisms of wrinkle formation in real tissue. There is sufficient interest in skin aging to ensure that the model will be assessed rigorously in the years ahead, however.

Despite the significance of biological wrinkle structures, much of the research in this area has relied on animal models including fruit flies, mice, and chickens, due to limitations in replicating wrinkle formation in vitro. As a result, the detailed processes behind wrinkle formation in living tissue remain largely unknown. Researchers addressed this limitation by developing an epithelial tissue model composed solely of human epithelial cells and extracellular matrix (ECM). By combining this model with a device capable of applying precise compressive forces, they successfully recreated and observed wrinkle structures in vitro that are typically seen in the gut, skin, and other tissues in vivo. This breakthrough allowed them, for the first time, to replicate both the hierarchical deformation of a single deep wrinkle caused by a strong compressive force and the formation of numerous small wrinkles under lighter compression.

The team also discovered that factors such as the porous structure of the underlying ECM, dehydration, and the compressive force applied to the epithelial layer are crucial to the wrinkle formation process. Their experiments revealed that compressive forces deforming the epithelial cell layer caused mechanical instability within the ECM layer, resulting in the formation of wrinkles. Additionally, they found that dehydration of the ECM layer was a key factor in the wrinkle formation process. These observations closely mirrored the effects seen in aging skin where dehydration of the underlying tissue layer leads to wrinkle development, providing a mechanobiological model for understanding wrinkle formation.

Link: https://www.postech.ac.kr/eng/the-mystery-of-human-wrinkles-what-do-the-cells-say/

The lessons to take away from the fact that therapies for type 2 diabetes lower risk of age-related disease in diabetic patient populations are much the same as the lessons to take away from the fact that weight loss drugs produce a reduction in age-related disease. Firstly the diabetic metabolism is harmful to the degree that is remains poorly controlled, and secondly excess weight is harmful. These lessons may have little relevance to the aging of thin, physically fit people, and diabetes-associated metabolic processes may not be the most important area of focus when it comes to the aging of thin, physically fit people.

The retrospective study looked at people with type 2 diabetes who started diabetes medication from 2014 to 2019 in South Korea. People taking SGLT2 inhibitors were matched with people taking other oral diabetes drugs, so the two groups had people with similar ages, other health conditions and complications from diabetes. Then researchers followed the participants to see whether they developed dementia or Parkinson's disease. Those taking the SGLT2 inhibitors were followed for an average of two years and those taking the other drugs were followed for an average of four years.

Among the 358,862 participants with an average age of 58, a total of 6,837 people developed dementia or Parkinson's disease during the study. For Alzheimer's disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10,000 person-years, compared to 63.7 cases for those taking other diabetes drugs. Person-years represent both the number of people in the study and the amount of time each person spends in the study. For vascular dementia, which is dementia caused by vascular disease, the incidence rate for people taking the SGLT2 drugs was 10.6 cases per 10,000, compared to 18.7 for those taking the other drugs. For Parkinson's disease, the incidence rate for those taking the SGLT2 drugs was 9.3 cases per 10,000, compared to 13.7 for those taking the other drugs.

After researchers adjusted for other factors that could affect the risk of dementia or Parkinson's disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer's disease and a 20% reduced risk of Parkinson's disease. Those taking the drugs had a 30% reduced risk of developing vascular dementia.

Link: https://www.eurekalert.org/news-releases/1057863

All cells secrete small membrane-wrapped packages of molecules, known as extracellular vesicles. How the contents and size and patterns of secretion change in response to circumstances remains poorly explored, but it is straightforward enough to harvest these extracellular vesicles from any population of cells grown in culture. It is plausible that near all current applications of stem cell therapy will be replaced by the use of extracellular vesicles derived from stem cells. The incentives point in that direction. Firstly, transplanted stem cells produce benefits via signaling, and most of that signaling is carried in secreted extracellular vesicles. Secondly, logistics of transport, storage, and quality control become easier and less costly when the therapy is harvested vesicles rather than cells.

The authors of today's open access paper make these points along the way to a discussion of the use of extracellular vesicles as a mode of therapy to treat neurodegenerative conditions. The most relevant of the mechanisms reliably affected by delivery of stem cell derived extracellular vesicles is inflammation. Neurodegenerative conditions have a strong inflammatory component, and lasting, unresolved inflammation of brain tissue is clearly associated with dysfunction and cognitive decline. Stem cell therapies and treatment with stem cell derived extracellular vesicles has a robust immunomodulatory effect, reducing chronic inflammation for some months even in people suffering the chronic inflammation of aging.

Stem cell-derived extracellular vesicles in the therapeutic intervention of Alzheimer's Disease, Parkinson's Disease, and stroke

As the aging population has steadily expanded in recent decades, the incidence of Alzheimer's Disease (AD), Parkinson's Disease (PD), and stroke has continued to rise annually. Stem cells (SCs), a category of undifferentiated cells with the potential for diverse specialization, self-replication, and self-renewal, represent a promising strategy. However, stem cell application encounters significant limitations due to the quality control, immune incompatibility, safety evaluation, ethical considerations and logical considerations, and tumorigenicity.

Extracellular vesicles (EVs) are small bilayer lipid structures discharged by most eukaryotic cells and tissue types. Possessing structures and properties akin to cells, EVs present a distinctive advantage. SC-EVs differ from stem cells in that they neither replicate nor undergo uncontrolled division, which helps avoid issues related to the use of stem cells, such as the risk of tumor formation and the challenges of successful engraftment.

Importantly, SC-EVs possess the ability to cross the blood-brain barrier (BBB) to generate therapeutic impacts within the brain. In addition, SC-EVs enhance the longevity and availability of therapeutic cargo in EV-based nanocarriers compared to EVs derived from other cells, thanks to the immuno-regulating characteristics acquired from the parent cells. It has been also indicated that SC-EVs contribute to favorable outcomes, including extending therapeutic effects, stimulating the immune system, enhancing quality control, and maintaining long-term storage at -80°C. Furthermore, biomedical engineering technology can additionally optimize both the exterior and interior of SC-EVs, enabling them to target particular cells, enhance efficient BBB crossing, and attain specific therapeutic results. Inspiringly, the treatment efficacy of SC-EVs has been extensively explored in diverse neurological disorder models.

In this review, we summarize the methods of obtaining SC-EVs, including the isolation and differentiation of stem cells, and isolation and purification of extracellular vesicles. Then, we review the functions of native SC-EVs, including neuroprotection, angiogenesis, and preservation of BBB integrity, alleviation of neuroinflammation, and other functions. However, there are drawbacks including poor targeting efficiency, inconsistent therapeutic outcomes, and limited output efficiency, which can be solved by precondition, loading drug, and modified surface. Consequently, we summarize the strategies for the engineering of SC-EVs and their applications in AD, PD, and stroke. Ultimately, we outline the challenges linked to these extracellular vesicles in clinical translation and offer potential solutions.

Every cell in the body contains hundreds of mitochondria, their primary task the generation of chemical energy store molecules to power cell processes. Mitochondrial function declines with age, a consequence of damage to mitochondrial DNA and maladaptive changes in gene expression in the cell. This loss of function is thought to be important in degenerative aging, leading to cell and tissue dysfunction and age-related conditions. Tissues with a high energy requirement, such as the brain and skeletal muscle, are the most affected. Thus all neurodegenerative conditions are likely driven in part by loss of mitochondrial function in the brain.

Progressive neurodegenerative diseases affect a significant proportion of the population; in a single year, there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases. Mitochondrial function, aging, and neurodegenerative processes appear to be intricately linked; central nervous system degeneration is a major feature of loss-of-function mitochondrial diseases, involving mutation of nuclear DNA or mitochondrial DNA. Meanwhile, mitochondrial dysfunction occurs during healthy aging and is further associated with several neurological diseases, including Alzheimer's disease (AD), Huntington's disease, Friedreich's ataxia, multiple sclerosis, motor neuron disease, Parkinson's disease (PD), and vanishing white matter disease (VWMD).

Aging increases neurodegenerative risk factors and processes, including progressively impaired cognitive and/or motor function due to cellular dysfunction, senescence, and/or neuronal death. Furthermore, impaired mitochondrial respiration, biogenesis, mitophagy, and axonal transport can be causative factors in dysfunctional protein synthesis, folding, aggregation, and trafficking, as well as inflammation, oxidative stress, and genomic instability. Thus, targeting mitochondrial function offers the premise of mitigating cellular degeneration. Furthermore, the cumulative impact of oxidative damage is exacerbated by the inherent susceptibility of mitochondrial DNA to reactive oxygen species (ROS)-induced mutations. Consequently, neurons appear to have an inherent susceptibility to mitochondrial dysfunction.

The interrelated nature of mitochondrial dysfunction and the inherent impact of energy dysregulation in cellular stress, proteotoxicity, and cell death implies that mitochondrial therapeutics may be beneficial for multiple neurodegenerative diseases and aging, i.e., to treat degeneration as a secondary mitochondrial disease. In an age of emerging gene and cell-based therapies, further research is warranted to explore the most effective mitochondrial-based strategies to slow neurodegenerative disease progression and aging.

Link: https://doi.org/10.4103/NRR.NRR-D-23-02106

Evidence suggests that Alzheimer's disease develops slowly over time for potentially decades prior to the emergence of symptoms. Researchers here made use of healthy patients with a familial history of Alzheimer's to assess the early stages of the development of the condition. The researchers measured the presence of protein aggregates and their interaction, as well as markers of brain activity. Their results show that even absent evident Alzheimer's disease, a greater presence of protein aggregates correlates with loss of cognitive function.

Amyloid-beta and tau proteins have long been associated with Alzheimer's disease. Researchers recruited 104 people with a family history of Alzheimer's. They scanned the participants' brains using a combination of positron emission tomography (PET) to detect the presence and location of the proteins and magnetoencephalography (MEG) to record brain activity in these regions. The scientists compared the results of the two scans and found that brain areas with increased levels of amyloid-beta showed macroscopic expressions of brain hyperactivity, reflected by increased fast- and decreased slow-frequency brain activity. For people with both amyloid-beta and tau in their brain, the pattern shifted towards hypoactivity, with higher levels of pathology leading to brain activity slowing.

Using cognitive tests, the team discovered that participants with higher rates of this amyloid-tau related brain slowing showed higher levels of decline in attention and memory. The findings suggest that the interplay between amyloid-beta and tau lead to altered brain activity before noticeable cognitive symptoms appear. In a follow up study, researchers plans to rescan the same participants over time to prove whether the accumulation of the two proteins promotes further slowing of brain activity, and whether this accurately predicts the cognitive evolution of the participants.

Link: https://www.eurekalert.org/news-releases/1058144

In innate immune cells known as macrophages are resident in tissues throughout the body in significant numbers. In the brain very similar cells called microglia are found. Macrophages (and microglia) are capable of undertaking a range of very different roles. On the one hand they can participate in the immune response, drive inflammatory signaling, and attack and destroy pathogens and cancerous, senescent, or otherwise errant cells. On the other hand they can be involved in dampening inflammation, clearing molecular waste and the debris of dead cells, coordinating regeneration from injury, and assisting other cell types in the growth and replacement needed to maintain functional tissues.

Which tasks a macrophage undertakes is reflected by its polarization and surface markers. M1 macrophages are pro-inflammatory and destructive, while M2 macrophages are anti-inflammatory helpers that assist in regeneration and tissue maintenance. While the reality of macrophage state is considerably less binary than this model, it is a helpful framework for the ways in which macrophages can be both help and hindrance.

Aging is characterized by a growing degree of chronic, unresolved inflammatory signaling. Culprits include the secreted cytokines of lingering senescent cells, but also a maladaptive reaction on the part of innate immune cells such as macrophages to the many forms of molecular damage that occur in cells and tissues with advancing age. Whether misplaced mitochondrial DNA fragments, misfolded protein aggregates, or the debris of dead cells, this all makes a contribution. Greater inflammation means more macrophages shifted into the M1 state, and that in turn has consequences when it comes to the maintenance of tissues.

Characterizing the skeletal muscle immune microenvironment for sarcopenia: insights from transcriptome analysis and histological validation

Age-related decline in skeletal muscle mass and function is a multifactorial phenomenon, characterized by the loss of muscle fibers and the atrophy of remaining fibers. Previous studies have highlighted the role of immune function changes in aging muscle, but the specific alterations in the immune microenvironment of skeletal muscle with age have yet to be fully understood. In this study, we utilized single nucleus RNA-seq analysis in combination with bulk RNA-seq to investigate the differences in cell composition and immune microenvironment between young and aged skeletal muscle tissue. Since macrophages were found to be the predominant immune cell population, we further identified a specific marker gene LYVE1 for macrophages and clustered them into subgroups. Additionally, we explored changes in cell-cell interactions between aged and young muscle. Furthermore, by analyzing bulk RNA-seq data, we examined the gene expression signature, functional differences, and infiltration characteristics of the young, aged, and sarcopenia groups, as well as the LYVE1-high and LYVE1-low groups.

Our analysis revealed that the sarcopenia group exhibited upregulation of several immune-related pathways, such as JAK-STAT, ERBB, and IL-2/IL-4 signaling pathways, in comparison to young controls. Previous studies have also linked these pro-inflammatory pathways to age-related muscle atrophy. We also discovered a crosstalk between immune cells and various non-immune cells within the muscle microenvironment. The results indicated that immune cells received signals from fibroblasts, endothelial cells, and other cell types, underscoring the significance of immune cells in the skeletal muscle microenvironment. Macrophages were found to be the predominant immune cell type in damaged muscles and played a crucial role in both the inflammation process and its resolution, contributing significantly to muscle repair. In response to anti-inflammatory cytokines, M1 macrophages transform into M2 macrophages in the later stages of skeletal muscle injury repair. Subsequently, these M2 macrophages along with resident M2 macrophages, facilitate the repair and regeneration processes by enhancing myoblast differentiation and vascularization, and stimulating fibro-adipogenic progenitor (FAP) cells to generate extracellular matrix. But macrophages in aged muscle are inclined to be polarized to a proinflammatory-phenotype, thereby negatively impacting the repair and regeneration capabilities of damaged muscle.

Neurodegenerative conditions driven by aggregation of misfolded or otherwise pathologically altered proteins can take a very long time to develop to the point of causing evident symptoms. There is a window of a decade or two in which researchers might develop sufficiently sensitive tests to detect the earliest stages of harmful protein aggregation. Demonstration technologies for early detection of Alzheimer's disease already exist. Here, researchers do much the same for Parkinson's disease, a condition characterized by the prion-like spread of misfolded α-synuclein through the central nervous system, but also into other, more readily accessible tissues such as skin.

"One known feature of Parkinson's is cell death resulting from aggregates of the alpha-synuclein protein. The protein begins to aggregate about 15 years before symptoms appear, and cells begin to die 5-10 years before diagnosis is possible with the means available today. This means that we have an extensive time window of up to 20 years for diagnosis and prevention, before symptoms appear. If we can identify the process at an early stage, in people who are 30, 40, or 50 years old, we may be able to prevent further protein aggregation and cell death."

Past studies have shown that alpha-synuclein aggregates form in other parts of the body as well, such as the skin and digestive system. In the current work the researchers examined skin biopsies from 7 people with and 7 people without Parkinson's disease. "We examined the samples using super-resolution imaging, combined with advanced computational analysis - enabling us to map the aggregates and distribution of alpha-synuclein molecules. As expected, we found more protein aggregates in people with Parkinson's compared to people without the disease. We also identified damage to nerve cells in the skin, in areas with a large concentration of the pathological protein. In future studies we will increase the number of samples and develop a machine learning algorithm to spot relatively young individuals at risk for Parkinson's."

Link: https://www.eurekalert.org/news-releases/1058080

The mechanisms of memory are energetically investigated, but remain incompletely understood. The better the understanding of the physical underpinnings of memory developed by the research community, the more likely it is to find effective ways to intervene in order to reverse the well-known age-related decline of memory function. The work here is one example of many lines of research aimed at better mapping the way in which memory is stored and maintained in the brain.

Working memory function is a critical cognitive ability that deteriorates with age following adulthood. Beyond its well-studied role in sensorimotor control, rhythmic neural activity in the beta band (15 to 25 Hz) has been suggested to regulate the status of working memory contents. Dynamics in beta-band activity reflect working memory processing. There is a decrease in beta activity when information needs to be maintained and an increase when information needs to be deleted. Maintenance-related beta decrease is primarily observed in the prefrontal cortex. By contrast, post-response beta increase is observed among task-related networks involving frontal and centroparietal regions, facilitating removal of both memory contents and associated representations such as motor plans after responses. Specifically, neurophysiological evidence from nonhuman primates demonstrated localized post-response beta increase at sites containing memory information during the time course of working memory clear-out. Whether such dynamics can be observed in human electrophysiology and how these neural dynamics change with age is unknown.

We adopted a novel approach to assess between- and within-group differences across ages. We combined cross-trial variability, which has largely been studied with broad-band EEG signal and fMRI hemodynamic responses, with rhythmic dynamics in the beta range, and examined them during both working memory maintenance and post-response deletion phases. Our novel analytical approach suggests that, when considering cross-trial fluctuations of beta power, variability explains individual differences in working memory performance during distinct phases for each age group.

Whereas individual memory performance of younger adults was explained by frontal beta variability during maintenance, memory performance of older adults was primarily explained by post-response beta variability. Thus, task-related cross-trial variability augments individual state-dependent characteristics and predicts behavioral differences within and across age groups. With the age-related dissociations between maintenance and post-response phases, beta variability may serve as an age-related, task-sensitive signature of individual differences in distinctive working memory computations.

Link: https://doi.org/10.1371/journal.pbio.3002784

Given the environment and state of medical technology over the past century, few people now live to be 100 years old. With yearly mortality rates approaching 50%, very few make it to 110. But in fact we don't know anywhere near as much as might be expected about the demographics of extreme old age. The data is near uniformly terrible in quality, the result of a number of factors. Firstly the state of century-old records is poor even in the most developed countries, so verifying age and identity can be costly and challenging. Secondly, a number of perverse incentives exist to produce incorrect data. Pensions fraud, for example, ensures that dead people remain alive in databases. Further there is a certain status to being extremely old in most societies, so some old people exaggerate their ages, enabled by poor or missing records.

This is all of great interest to demographers, the question of bad data and how to compensate for the problems or fix them. But from the perspective of what we intend to do about aging, whether we choose to earnestly treat aging as a medical condition, how researchers might develop rejuvenation therapies based on repair of cell and tissue damage, the present demographics of extreme old age do not matter. At all. The research community knows more than enough about the mechanisms of aging to work on potential rejuvenation therapies. Improving the demographics of late life survival will add very little to that body of knowledge.

The global pattern of centenarians highlights deep problems in demography

The measurement of human ages, and by extension age-specific rates of any quantity, relies almost universally upon a single measurement system: the globally-incomplete paperwork-based system of documentary evidence known as vital registration. Despite age being the single most important risk factor for human health, along with gender, there has been no accurate and independently metric to validate human age measurements. If a developmentally mature person walks into a clinical setting with no paperwork, for example, there has been no independent or reproducible test available to measure their chronological age. As such, if age-based paperwork consistently records an incorrect age, there is no method by which that error can be detected because there is, or rather has been, no independently reproducible scientific method available for discovering such errors.

As a result, globally diverse document-based systems of vital registration are not subject to any document-independent technical validation or calibration. Systematic errors or error-generating processes that modify age records, from heavily biased or systemic errors to simple typographic mistakes, can therefore remain undetected indefinitely. Despite some scepticism on the reliability of age data this situation has been long ignored: first on the basis of an untestable assumption that such errors must be rare, and second on the seemingly reasonable statistical grounds that - if vital registration errors are assumed to be sufficiently rare and random - they may be safely ignored by fitting random error terms within a statistical model.

Recent theoretical work has shown that neither case seems to be a valid assumption especially at older ages. In survival processes, age-coding errors accumulate non-randomly with age - even when initial rates of error are vanishingly low, symmetrically distributed, and random - through a process that can substantially distort late-life data and massively inflate the frequency of errors at certain ages.

The underlying theoretical reason is simple. Consider, for example, a population of one million fifty-year-old people, into which a hundred 40-year-olds are accidentally included through age-coding errors: an initial error rate of 0.01% or one in every ten thousand. The paperwork of these 40-year-olds accidentally records them as aged 50 years - a surprisingly common mistake - and these 'young liar' errors appear, officially and on paper, as 50-year-olds. As the two cohorts age, the 'young liar' errors are less than half as likely to die as the actual 50-year-olds - because they are biologically 10 years younger - and errors therefore constitute a growing fraction of the population with age. In typical human populations, error rates will grow at an approximately exponential rate with age due to the better survival of 'young liars.' By age 85 more than half of the population becomes errors, by age 100 'young liar' errors constitute the entire population: a kind of error explosion caused by the asymmetrically better survival of 'young liars.'

Combined with the historical lack of paperwork-independent methods to validate and correct paper records, this simple theoretical process raises an uncomfortable possibility: that extreme age records may be dominated by undetected errors. Analysis of 236 nations or states across 51 years reveals that late-life survival data is dominated by anomalies at all scales and in all time periods. Life expectancy at age 100 and late-life survival from ages 80 to 100+, which we term centenarian attainment rate, is highest in a seemingly random assortment of states. The top 10 'blue zone' regions with the best survival to ages 100+ routinely includes Thailand, Kenya and Malawi - respectively now 212th and 202nd in the world for life expectancy, the non-self-governing territory of Western Sahara, and Puerto Rico where birth certificates are so unreliable they were recently declared invalid as a legal document. These anomalous rankings are conserved across long time periods and multiple non-overlapping cohorts, and do not seem to be sampling effects. Instead these patterns suggest a persistent inability, even for nation-states or global organisations, to detect or measure error rates in human age data, with troubling implications for epidemiology, demography, and medicine.

Epigenetic clocks are produced by the application of machine learning techniques to epigenetic data obtained from people at various ages. Characteristic changes in DNA methylation take place with advancing age, and thus can be used to provide an assessment of biological age. Epigenetic age acceleration is the state of having an epigenetic age, as measured by an epigenetic clock, that is higher than chronological age. Numerous studies have shown that this acceleration correlates with a higher risk of age-related disease and mortality.

We analyzed data from 2,105 participants to the 1999-2002 National Health and Nutrition Examination Survey aged ≥50 years old who were followed for mortality through 2019. Epigenetic age accelerations (EAAs) were calculated from Horvath, Hannum, SkinBlood, Pheno, Zhang, Lin, Weidner, Vidal-Bralo and Grim epigenetic clocks regressed on chronological age. Using cox proportional hazards regression, we estimated the hazard ratio (HR) for the association of EAA (per 5-year) and the DunedinPoAm pace of aging (per 10% increase) with overall, cardiovascular, and cancer mortality, adjusting for covariates and white blood cell composition.

During a median follow-up of 17.5 years, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA (HR: 1.50) followed by Hannum (HR: 1.16), Pheno (R: 1.13), Horvath (HR: 1.13) and Vidal-Bralo (HR: 1.13) EAAs. Grim EAA predicted cardiovascular mortality (HR: 1.55), whereas Hannum (HR: 1.24), Horvath (HR: 1.18) and Grim (HR: 1.37) EAAs predicted cancer mortality. DunedinPoAm pace of aging was associated with overall (HR: 1.23) and cardiovascular (HR: 1.25) mortality.

Link: https://doi.org/10.1101/2024.08.21.24312373

Bone extracellular matrix is constantly remodeled, created by osteoblast cells and removed by osteoclast cells. With age, these activities become unbalanced in favor of osteoclasts. The result is a progressive loss of bone mineral density and ultimately osteoporosis. Approaches to therapy focus on restoring the balance of activity, often by increasing osteoblast activity. The basis for treatment noted here is an example of the type, in which researchers influence the regulation of osteoblast population size to increase bone extracellular matrix deposition.

Osteoporosis and other metabolic bone diseases are prevalent in the aging population. While bone has the capacity to regenerate throughout life, bone formation rates decline with age and contribute to reduced bone density and strength. Identifying mechanisms and pathways that increase bone accrual in adults could prevent fractures and accelerate healing. G protein-gated inwardly rectifying K+ (GIRK) channels are key effectors of G protein-coupled receptor signaling. Girk3 was recently shown to regulate endochondral ossification. Here, we demonstrate that deletion of Girk3 increases bone mass after 18 weeks of age. Male 24-week-old Girk3-/- mice have greater trabecular bone mineral density and bone volume fraction than wildtype (WT) mice.

Osteoblast activity is moderately increased in 24-week-old Girk3-/- mice compared to WT mice. In vitro, Girk3-/- bone marrow stromal cells (BMSCs) are more proliferative than WT BMSCs. Calvarial osteoblasts and BMSCs from Girk3-/- mice are also more osteogenic than WT cells, with altered expression of genes that regulate the wingless-related integration site (Wnt) family. Wnt inhibition via Dickkopf-1 (Dkk1) or β-catenin inhibition via XAV939 prevents enhanced mineralization, but not proliferation, in Girk3-/- BMSCs and slows these processes in WT cells. Finally, selective ablation of Girk3 from osteoblasts and osteocytes is sufficient to increase bone mass and bone strength in male mice at 24 weeks of age. Taken together, these data demonstrate that Girk3 regulates progenitor cell proliferation, osteoblast differentiation, and bone mass accrual in adult male mice.

Link: https://doi.org/10.1093/jbmrpl/ziae108

Hundreds of mitochondria can be found in every cell in the body. Their primary purpose to create adenosine triphosphate (ATP), a chemical energy store molecule necessary for cell function. Mitochondria are the distant descendants of ancient symbiotic bacteria, now fully integrated into the cell. As such, mitochondria have their own circular genome, the mitochondrial DNA, and despite being a component of the cell still behave very much like bacteria: dividing, fusing together, swapping component parts. Over time, near all mitochondrial DNA has migrated into the nuclear genome, the result of unlikely mutational accidents. On a long enough timescale, even the unlikely becomes frequent. Still, some critical mitochondrial genes have proven resistant to this process, and they remain in place, in the mitochondria, to make up the small mitochondrial genome.

The problem with the existence of mitochondrial DNA is that it is (a) essential to mitochondrial function and (b) both far more prone to damage and far less well guarded and repaired than is the case for nuclear DNA. Deletion mutations in mitochondrial DNA can produce dysfunctional mitochondria that outcompete their undamaged peers, creating a malfunctioning cell overtaken by disruptive mitochondria, a cell that becomes actively harmful to surrounding tissue. The accumulation of lesser forms of mitochondrial DNA damage, repeated countless times throughout the cells of the body, is still thought to contribute to the age-related loss of mitochondrial function.

Researchers have given considerable thought as to how to fix this issue. Replace the mitochondria with new ones harvested in bulk from suitable cell lines; tinker with the mitochondrial quality control system of mitophagy to make it more efficient; cellular reprogramming to recreate the processes of early embryonic development that appear to clear out malfunctioning mitochondria; and of course allotopic expression. Allotopic expression is the goal of completing the work carried out to date by evolution by creating copies of the remaining mitochondrial genes in the nuclear genome, suitably altered to ensure that proteins are delivered to the mitochondria where they are needed. In effect, producing a backup source of vital proteins to ensure that mitochondrial DNA damage doesn't lead to dysfunction.

How Secure a Mitochondrial Backup is Allotopic Expression?

Doesn't the existence of mutational damage in nuclear DNA undermine the concept of nuclear backup copies as a solution to mitochondrial DNA damage? In fact engineering backup copies of the mutation-prone mitochondrial genes into the safe harbor of the nucleus is our strongest strategy for protecting the body from large mitochondrial deletion mutations. It's these deletions - particularly one that is found in so many cells that it is literally called "the common deletion" - that are most tightly linked to aging and diseases and disabilities of aging like Alzheimer's and Parkinson's diseases and the loss of functioning muscle fibers and strength with age. The concept of these engineered backup copies (technically, allotopic expression (AE)) was in fact the first of the proposed Strategies for Engineered Negligible Senescence (SENS) rejuvenation biotechnologies.

There are several things about the nature of the problem and the tools we have at our disposal that make AE not just viable but an enduring solution for mitochondrial mutations, even though nuclear DNA is also susceptible to free radical damage just like mitochondrial DNA is. The first is the sheer amount of oxidative damage in mitochondrial versus nuclear DNA. The mitochondrial DNA's exceptional vulnerability to free radical damage results, first and foremost, from its being located so close to the mitochondrial energy-production machinery, which is one of the major sources of free radical production in our bodies. We can now say with great confidence that the impact of mitochondrial free radicals on the nuclear DNA is negligible.

Even when mutations do occur in the nuclear DNA, the consequences are less likely to be harmful than those in the mitochondrial DNA. This is true in a couple of different senses. First, most mutations in the nuclear DNA are self-contained, causing defects in the proteins produced by one or a small number of genes that are directly damaged. By contrast, the "common deletion" mutation in mitochondrial DNA not only wipes out several genes that code directly for proteins, but also the genes that encode some of the machinery that the mitochondria need to assemble the proteins coded for by any gene in the mitochondrial genome. Without this machinery, the mitochondria can't produce any of the proteins encoded in the mitochondrial genome, including proteins whose genes are completely intact. There is no parallel catastrophic failure in garden-variety nuclear mutations.

A second way that mutations in the nuclear DNA are less likely to cause problems than mitochondrial DNA mutations derives from how much less of its nuclear DNA a given cell type needs to carry out its function. The mitochondrial DNA is a very lean operating system: almost every letter in its code carries essential instructions for producing some machinery that the mitochondria require for their function throughout life. By contrast, each cell houses lots of DNA in its nucleus that it can do without, or that can suffer a significant amount of mutation without harming the cell.

But still, our AE copies of mitochondrial genes are likely to suffer disabling mutations at some point in the future, even if that point is many times further away than anyone alive today has yet lived. Those mutations might even spread into tissue if they occur in stem cells. What can we anticipate our future options to fix the problem to be? The most obvious approach is a "simple" do-over: put another set of AE mitochondrial genes in the nucleus of our cells. A gene therapy given once can be given again.

An important part of the process of aging is a dysregulation of all of the finely tuned control and feedback systems that connect the different organs of the body. As one organ falters, there are indirect harmful effects on other organs. For example, distinct portions of the brain actively modulate the operation of metabolism elsewhere in the body in many different ways. The degenerative aging of brain tissue affects these communications, and that gives rise to issues outside the brain - just as aging of organs outside the brain can cause harm to the brain itself. Everything is connected.

Many studies have shown that longevity is regulated through cell non-autonomous signaling mechanisms by pathways originating in central nervous system neurons. These signaling pathways, which affect peripheral tissues, can significantly influence organismal health and longevity. Enhancement or suppression of these signaling pathways in central nervous system neurons leads to functional changes within the neurons (cell autonomous process) and transmits signals to the periphery to modulate its functions (cell non-autonomous process). For instance, in the nematode worm Caenorhabditis elegans, ASI amphid chemosensory neurons are important to maintain proper metabolic status, and possibly longevity. Ablation of ASI neurons completely suppresses the effect of lifespan extension induced by dietary restriction, suggesting that ASI neurons are required for the longevity effect of dietary restriction.

In the fly Drosophila melanogaster, neuronal activation of AMPK or Atg1, an autophagy-specific protein kinase, induces autophagy in the brain to slow aging and improves various parameters of healthspan. Drosophila insulin-like peptides are implicated in mediating the inter-tissue responses between the nervous system and the intestines. Furthermore, modifying mitochondrial function in neurons that influence aging and fly longevity also affects cells through cell non-autonomous mechanisms. A recent study demonstrated that the overexpression of hedgehog signaling, which is present in the glial cells of an adult fly, rescues proteostasis defects and the reduced lifespan in the glia of hedgehog mutant flies.

In mammals, increasing evidence highlights the role of the brain in the regulation of aging and longevity through cell non-autonomous signaling mechanisms. Specifically, the hypothalamus stands out as one of the most active regions involved in these signaling processes related to aging and longevity. In this review, we summarize the multiple signaling pathways in the hypothalamus that convey signals from the brain to peripheral organs and modulate aging and mammalian longevity. We describe how the structure and function of the hypothalamus are conserved across species and how these aspects are altered with age. Finally, we discuss some future perspectives on aging research that focus on the hypothalamus.

Link: https://doi.org/10.1186/s12576-024-00934-3

It would be useful to produce a body of work that assesses the results of beneficial lifestyle choices on biomarkers that are usually only assessed in the context of other, usually pharmacological interventions. It remains the case that calorie restriction and exercise outperform most of the other options presently on the table when it comes to slowing or turning back the progression of degenerative aging. This is a dismal state of affairs, but perhaps more data will help to spur the creation of better approaches to therapy.

It has recently been highlighted how a short healthy life-style program (LSP) can improve the functional outcomes of older people admitted to a Long-Term Care (LTC) facility. Although it is known that life-style medicine-based interventions can exert anti-aging effects through the modulation of oxidative stress and mitochondrial function, the mechanisms underlying the aforementioned effects have not been clarified, yet. For this reason, in this study, the outcomes were focused on the investigation of the possible mechanisms underlying the benefits of a short LSP in older people. This was achieved by examining circulating markers of oxidative stress and immunosenescence, such as Tymosin β (Tβ4), before and after LSP and the effects of plasma of older people undergone or not LSP on endothelial cells.

Fifty-four older people were divided into two groups (n = 27 each): subjects undergoing LSP and subjects not undergoing LSP (control). The LSP consisted of a combination of caloric restriction, physical activity, and psychological intervention and lasted 3 months. Plasma samples were taken before (T0) and after LSP (T1) and were used to measure thiobarbituric acid reactive substances (TBARS), 8-hydroxy-2-deoxyguanosine (8OHdG), 8-Isoprostanes (IsoP), glutathione (GSH), superoxide dismutase (SOD) activity and Tβ4. In addition, plasma was used to stimulate human vascular endothelial cells (HUVEC), which were examined for cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), and mitochondrial ROS (MitoROS) release.

At T1, in LSP group we did not detect the increase of plasma TBARS and IsoP, which was observed in control. Also, plasma levels of 8OHdG were lower in LSP group vs control. In addition, LSP group only showed an increase of plasma GSH and SOD activity. Moreover, plasma levels of Tβ4 were more preserved in LSP group. Finally, at T1, in HUVEC treated with plasma from LSP group only we found an increase of the mitochondrial membrane potential and a reduction of ROS and MitoROS release in comparison with T0. The results of this study showed that a short LSP in older persons exerts antiaging effects by modulating oxidative stress at cellular levels.

Link: https://doi.org/10.1016/j.heliyon.2024.e35850

Senolytic drugs clear lingering senescent cells from aged tissues. The mechanisms are quite diverse, but most senolytic therapies either sabotage the ability of senescent cells to resist their primed apoptosis machinery, thus promoting programmed cell death, or encourage the immune system to more rapidly and aggressively destroy senescent cells. Interestingly, comparatively little research and development has taken place on topical senolytics; one might look at OneSkin as an example, but these efforts are far outnumbered by programs aiming to produce senolytic drugs that affect the whole of the body, or at least major internal organs.

In today's open access paper, researchers report on the topic use of the senolytic drug navitoclax (or ABT-263). Navitoclax is a larger molecule than one would expect to be able to pass the skin barrier, but here the researchers use DMSO as a permeability enhancer and it appears to work. Using aged mice, the researchers demonstrate reduced markers of cellular senescence in skin and enhanced wound healing following a topical senolytic treatment.

Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing

Senescent cells (SnC) accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period.

Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure.

In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

The old are more vulnerable to infectious disease as a result of the age-related decline of the immune system, but other mechanisms can also play a role. For example, leakage of the blood-brain barrier can allow pathogens access to the brain, a pathway not open in youth. Neurocryptococcosis is an example of an infectious condition of the central nervous system in which the pathogen is a fungus; it is more common in older people, and researchers here discuss why this is the case.

Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS.

Although clinical evidence has pointed out the higher prevalence of neurocryptococcosis in older compared to younger adults, the exact mechanisms underlying this epidemiological evidence still need to be elucidated in depth. However, it is very plausible that age-related disruption of innate and acquired immune response may increase the risk of both cryptococcaemia and neurocryptoccocis and may enhance the direct deleterious effects of cryptococcal infection. Aging-induced defective clearing activity of alveolar macrophages, along with increased polarization into pro-inflammatory M1 cells and increased activation of Th2 responses, are thought to contribute to increased cryptococcal damage. Overall, age-associated alterations in innate immune responses may increase the risk of ineffective cryptococcal clearance, severe pulmonary disease, and dissemination to the CNS.

Link: https://doi.org/10.3389/fimmu.2024.1410090

The evidence for metformin to even modestly slow aging is not robust, certainly not when compared to the evidence for rapamycin. The mouse lifespan data for metformin treatment is all over the map, and the human data in diabetic patients has issues. Still, some studies show benefits, including the recently published non-human primate study noted here. One critique is that the researchers developed novel aging clocks to assess biological age, rather than use a standard mammalian clock, but one can't argue with the data on cognitive function and potential protective mechanisms.

Metformin has been used for more than 60 years to lower blood-sugar levels in people with type 2 diabetes - and is the second most-prescribed medication in the United States. The drug has long been known to have effects beyond treating diabetes, leading researchers to study it against conditions such as cancer, cardiovascular disease, and ageing. Data from worms, rodents, flies and people who have taken the drug for diabetes suggest the drug might have anti-ageing effects. But its effectiveness against ageing had not been tested directly in primates, and it is unclear whether its potential anti-ageing effects are achieved by lowering blood sugar or through a separate mechanism.

This led researchers to test the drug on 12 elderly male cynomolgus macaques (Macaca fasciucularis); another 16 elderly monkeys and 18 young or middle-aged animals served as a control group. Every day, treated monkeys received the standard dose of metformin that is used to control diabetes in humans. The animals took the drug for 40 months, which is equivalent to about 13 years for humans. Over the course of the study, researchers took samples from 79 types of the monkeys' tissues and organs, imaged the animals' brains and performed routine physical examinations. By analysing the cellular activity in the samples, the researchers were able to create a computational model to determine the tissues' 'biological age', which can lag behind or exceed the animals' age in years since birth.

The researchers observed that the drug slowed the biological ageing of many tissues, including from the lung, kidney, liver, skin and the brain's frontal lobe. They also found that it curbed chronic inflammation, a key hallmark of ageing. The study was not intended to see whether the drug extended the animals' lifespans; previous research has not established an impact on lifespan but has shown lengthened healthspan - the number of years an organism lives in good health. The researchers also identified a potential pathway by which the drug protects the brain: it activates a protein called NRF2, which safeguards against cellular damage triggered by injury and inflammation.

Link: https://doi.org/10.1038/d41586-024-02938-w

Some species, including a number of highly regenerative species, exhibit little to no age-related decline over much of their life span. Much of the effort put into exploring the comparative biology of aging has focused on these species, in search of specific differences in their cellular biochemistry that might explain why they age so differently from most animals. Negligibly senescent species tend to be long-lived in comparison to normally aging neighboring species in the tree of life, consider naked mole rats versus mice for example, but the question of how they exhibits little degenerative aging in later life may be distinct from the question of why they exhibit a specific life span.

The development of epigenetic clocks and other aging clocks derived from omics data continues apace, gathering increased interest and funding. To be able to measure biological age from a tissue sample is a strong incentive, as this capability would greatly speed up the development of effective therapies to treat aging. There is some way to go yet before aging clocks can be trusted to reflect the results of a given potential therapy, however. It is unclear as to how the measured omics markers connect to aging and specific aspects of aging. But why not apply these technologies to negligibly senescent species and see what the results look like? Hence researchers here attempt to build an epigenetic clock for the axolotl, a highly regenerative and negligibly senescent species of salamander. The results are interesting, to say the least.

Axolotl epigenetic clocks offer insights into the nature of negligible senescence

Salamanders such as the axolotl (Ambystoma mexicanum) are the evolutionarily closest organisms to humans capable of regenerating extensive sections of their body plan, including parts of their eyes, lungs, heart, brain, spinal cord, tail, and limbs throughout their lives, constituting valuable models for regeneration studies. Yet, urodele amphibians are also characterised by an apparent lack of physiological declines through lifespan, indefinite regenerative capacity, extraordinary longevity, and defiance of the Gompertz law of mortality, key features of negligible senescence. Their long lifespans and lack of experimental tractability have historically restricted their use in ageing studies. However, recent technological advances have enabled the axolotl as a tractable model system.

Throughout life, axolotls exhibit several age-defying traits, including dermal thickening, progressive skeletal ossification, and cancer resistance. Further, their tissues do not accumulate senescent cells with age, thereby circumventing a major hallmark of ageing and driver of age-related disorders, in keeping with their proposed negligible senescence status. Yet, whether axolotls exhibit signs of molecular ageing remains unknown.

Changes in the methylation level of cytosines within CpG dinucleotides constitute a primary hallmark of molecular ageing. Indeed, age-related changes in DNA methylation (DNAm) occur across animal species, including mammals, birds, fishes and amphibians. More recently, the Mammalian Methylation Consortium has confirmed that age-related gains in methylation can be observed at target sites of the Polycomb Repressive Complex 2 (PRC2), which catalyses the tri-methylation of lysine 27 on histone H3 (H3K27me3) in all mammalian species. DNA methylation at PRC2 target sites may constitute a universal biomarker of aging and rejuvenation in mammalian systems.

Multivariate regression models based on the methylation status of multiple CpG sites provide accurate age estimators, commonly known as 'epigenetic clocks,' in mammalian species. Initially restricted to humans and mice, the identification of highly conserved CpGs facilitated the construction of multispecies clocks. Here, we conduct DNA methylation profiling of axolotl tissues at CpGs associated with ageing across mammalian and amphibian species. We develop axolotl epigenetic clocks at both pan-tissue and single tissue levels and uncover that axolotls exhibit conserved epigenetic ageing traits during early life but not thereafter, deviating from the established notion of organismal ageing. We reveal that, in contrast to mammals, the axolotl methylome is remarkably stable and does not exhibit substantial shifts at either global or PRC2-associated gene levels late in life.

Autophagy is the name given to a collection of complex maintenance processes responsible for recycling damaged and excess protein structures in the cell. Upregulation of autophagy is one of the more important responses to cell stress, and is involved in the slowing of aging produced by the practice of calorie restriction. It is reasonable to think that more autophagy means less damage and dysfunction in cells at any given time, and, when sustained over time for all of the cells in an organism, this helps to fend off some modest fraction of the damage and dysfunction of degenerative aging. Various measures of autophagy indicate that its efficiency declines with age, however. As for all complex processes in the cell, aging produces disarray. Why exactly is this the case? Autophagy is sufficiently complicated for current answers to that question to be incomplete, a work in progress.

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age.

In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.

Link: https://doi.org/10.3390/cells13161364

Researchers here show that upregulation of a specific microRNA, miR-29, occurs during aging. When induced artificially, increased expression of miR-29 produces an aging-like disruption of metabolism and early mortality. The research community doesn't have a good understanding of why miR-29 expression increases with age, with most research focused on downstream consequences. Aging as a whole no doubt includes many maladaptive changes in gene expression, some of which are likely to be more important than others. How large a gain in healthy life span can reasonably be achieved by blocking only a select few of these changes with suitable drug technologies? That remains to be determined.

Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear. A miRNA known to be upregulated during both normal and premature aging is miR-29. We find miR-29 to also be among the top miRNAs predicted to drive aging-related gene expression changes. We show that partial loss of miR-29 extends the lifespan of Zmpste24-/- mice, an established model of progeria, indicating that miR-29 is functionally important in this accelerated aging model.

To examine whether miR-29 alone is sufficient to promote aging-related phenotypes, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). miR-29 overexpression is sufficient to drive many aging-related phenotypes and led to early lethality. Transcriptomic analysis of both young miR-29TG and old wild type mice reveals shared downregulation of genes associated with extracellular matrix organization and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. These results highlight the functional importance of miR-29 in controlling a gene expression program that drives aging-related phenotypes.

Link: https://doi.org/10.1038/s42003-024-06735-z

The axons connecting neurons of the nervous system are sheathed in a layer of myelin. This myelination of axons is necessary for the transmission of electrochemical signals through the nervous system. When the myelin layer becomes extensively damaged, whatever the cause, the result is profoundly disabling conditions such as multiple sclerosis. Over the course of late life aging, the myelin sheathing of axons is disrupted to a lesser but still meaningful degree. It is thought that age-related degradation of myelin in the brain contributes to cognitive impairment, for example. This is why it is worth keeping an eye on progress towards novel therapies that might induce repair of myelin.

The myelin sheathing of axons is maintained by a population of cells known as oligodendrocytes. In today's open access paper, researchers outline their discovery of a regulator of this population size. Expression of C1ql1 regulates the pace at which oligodendrocytes are produced from a population of progenitor cells; the more oligodendrocytes, the greater the repair of damaged myelin. This offers a potential point of intervention, a basis for therapies that work by increasing C1ql1 expression. Such therapies may be useful not just for the treatment of demyelinating conditions, but also offer a way to reverse the age-related damage to myelin.

C1ql1 expression in oligodendrocyte progenitor cells promotes oligodendrocyte differentiation

The myelination of axons by oligodendrocytes in the central nervous system (CNS) is essential for proper nervous system function. Mature oligodendrocytes are post-mitotic and arise through a stepwise differentiation process from resident oligodendrocyte progenitor cells (OPCs). Oligodendrocytes that arise during development may have very long lifespans, perhaps equal to the longevity of the animal itself; it is, therefore, curious that a remarkable ~5% of all cells in the adult CNS remain as OPCs. This resident pool of OPCs represents a potential source of new oligodendrocytes important for cognition and learning and also to replace those lost to injury or inflammation in diseases such as multiple sclerosis (MS).

Proteins of the C1q/tumor necrosis factor (TNF) superfamily have recently gained attention for their role at neuronal synapses. Among these, the complement C1q-like (C1QL) proteins, encoded by four paralogous genes (C1ql1, C1ql2, C1ql13, C1ql14), have drawn significant interest. In the CNS, C1QL proteins are typically expressed in a small subset of neurons, are secreted from pre-synaptic terminals, reside in the synaptic cleft, and function to promote synapse formation and/or maintenance. We have determined that C1QLs bind to a post-synaptically localized G protein-coupled receptor (GPCR) called adhesion GPCR B3 (ADGRB3).

C1QL1 and ADGRB3 likely have pleiotropic functions beyond neuron-neuron synapses. We have recently shown that most C1QL1-expressing cells in the brain co-express the transcription factor OLIG2, indicating that they are of the oligodendrocyte lineage. This suggests that C1QL1-ADGRB3 signaling from glia is associated with remyelination potential. Therefore, we investigated whether C1QL1 has a function in regulating OPC differentiation. We show that C1ql1 is expressed by OPCs, and in most brain regions, is the only cell type expressing C1ql1. To uncover the function of C1QL1, we created OPC-specific conditional knockout (cKO) mice and found that C1ql1 removal from OPCs causes a developmental delay in oligodendrocyte cell density and myelination, but mice recover by adulthood. After mice were challenged by cuprizone-induced demyelination, we found cKO mice had a reduced or delayed oligodendrocyte density and remyelination recovery, while a virus that we designed to overexpress C1QL1 caused an increase in oligodendrocyte density and myelination during recovery.

To study possible mechanistic explanations for these phenotypes, we used primary OPC cultures in vitro and found that C1QL1 levels can bidirectionally regulate the extent of OPC differentiation into oligodendrocytes. Our combined results suggest that C1QL1 signaling may have therapeutic potential for treating demyelinating diseases such as MS.

Epidemiological data clearly shows that particulate air pollution increases late life mortality and incidence of age-related disease. The primary mechanism is thought to be an increase in the chronic inflammation of aging induced by the interaction between inhaled particulates and lung tissue. Here, researchers focus on the degree to which cellular senescence mediates the harms caused by particulates. The advent of senolytic drugs capable of selectively clearing senescent cells from tissues offer a change to reduce some of the consequences of particulate air pollution.

Exposure to particulate matter 2.5 (PM2.5) accelerates aging, causing declines in tissue and organ function, and leading to diseases such as cardiovascular, neurodegenerative, and musculoskeletal disorders. PM2.5 is a major environmental pollutant and an exogenous pathogen in air pollution that is now recognized as an accelerator of human aging and a predisposing factor for several age-related diseases.

Approximately 85% of the global population is exposed to air pollution levels above safe limits. Long-term exposure to air pollutants is associated with an increased risk of adverse health outcomes such as dementia, type 2 diabetes, cardiovascular diseases, and lung cancer. Air pollution is now the fourth largest global burden of disease. Therefore, it is imperative to scrutinize the role of air pollution in aging and age-related diseases.

In this paper, we seek to elucidate the mechanisms by which PM2.5 induces cellular senescence, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, and age-related diseases. Our goal is to increase awareness among researchers within the field of the toxicity of environmental pollutants and to advocate for personal and public health initiatives to curb their production and enhance population protection. Through these endeavors, we aim to promote longevity and health in older adults.

Link: https://doi.org/10.1016/j.ecoenv.2024.116920

A dozen or more different ways to selectively destroy lingering senescent cells in aged tissue are presently under preclinical or clinical development to produce senolytic drugs. Meanwhile, the research community is enaged in to better understand the biochemistry of senescent cells, in search of more ways to destroy them. The diversity of senescent cell biochemistry and the usual challenges of drug delivery to different organs within the body suggests that a mature senolytic toolkit may consist of many different therapies optimized for different tissue types and age-related conditions.

The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related pathologies. Targeting senescence-associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence-specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or "surfaceome", in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types.

Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age-related diseases.

Link: https://doi.org/10.1111/acel.14312

The gut microbiome is made up of a diverse collection of microbial species. Some are necessary for good health, some are actively harmful, and some just along for the ride. The immune system does its best to try to keep the balance favorable. The balance of hundreds of different populations making up the gut microbiome is resilient to short-term change induced by diet, probiotics, antibiotics, and the like; it will bounce back to where it was before quite quickly. The gut microbiome can and does change to significant degrees over the course of years and decades, however. The gut microbiome ages, the numbers of inflammatory and harmful microbes growing at the expense of microbes that produce beneficial metabolites. This may be driven in part by the growing incapacity of the immune system in older people, but significant changes in the gut microbiome appear too early in adult life for this to be the only mechanism in play.

It has been noted that long-lived individuals appear to have distinct differences in the composition of the gut microbiome. This may be because having a less inflammatory gut microbiome tips the scales in the direction of lower mortality and lower incidence of age related disease. The chronic inflammation of aging is destructive and undesirable, and less of it is a good thing. Unfortunately even a small increase in the odds of survival to centenarian status resulting from a particular configuration of the gut microbiome would lead to that configuration occurring often in centenarians. Better data than correlation is needed, and the way to obtain that data is to build therapies capable of inducing lasting change in the gut microbiome. At present only a few approaches are well demonstrated to work: (a) inducing the immune system into better garden the microbiome, such as via flagellin immunization, and (b) fecal microbiota transplantation. Both of these are blunt tools, incapable of producing specific population changes. Better approaches are needed.

Consistent signatures in the human gut microbiome of longevous populations

Gut microbiota of centenarians has garnered significant attention in recent years, with most studies concentrating on the analysis of microbial composition. However, there is still limited knowledge regarding the consistent signatures of specific species and their biological functions, as well as the potential causal relationship between gut microbiota and longevity. To address this, we performed the fecal metagenomic analysis of eight longevous populations at the species and functional level, and employed the Mendelian randomization (MR) analysis to infer the causal associations between microbial taxa and longevity-related traits.

We observed that several species including Eisenbergiella tayi, Methanobrevibacter smithii, Hungatella hathewayi, and Desulfovibrio fairfieldensis were consistently enriched in the gut microbiota of long-lived individuals compared to younger elderly and young adults across multiple cohorts. Analysis of microbial pathways and enzymes indicated that E. tayi plays a role in the protein N-glycosylation, while M. smithii is involved in the 3-dehydroquinate and chorismate biosynthesis. Furthermore, H. hathewayi makes a distinct contribution to the purine nucleobase degradation I pathway, potentially assisting the elderly in maintaining purine homeostasis. D. fairfieldensis contributes to the menaquinone (vitamin K2) biosynthesis, which may help prevent age-related diseases such as osteoporosis-induced fractures.

According to MR results, Hungatella was significantly positively correlated with parental longevity, and Desulfovibrio also exhibited positive associations with lifespan and multiple traits related to parental longevity. Additionally, Alistipes and Akkermansia muciniphila were consistently enriched in the gut microbiota of the three largest cohorts of long-lived individuals, and MR analysis also suggests their potential causal relationships with longevity. Our findings reveal longevity-associated gut microbial signatures, which are informative for understanding the role of microbiota in regulating longevity and aging.

The study noted here is one of numerous similar efforts to analyze data on the life span of professional athletes. The data set used is very heavily weighted towards men, so the results for women in this study should probably be taken with a grain of salt. With a few odd exceptions, the results are generally consistent with what has been seen in the past, in that professional participants in sports requiring a high level of physical fitness exhibit a longer life span than the average for the general population. Correlational studies cannot demonstrate causation, but there is plenty of evidence from animal studies for physical fitness and the exercise needed to maintain physical fitness to act in ways that slow the progression of degenerative aging.

The human lifespan is influenced by various factors, with physical activity being a significant contributor. Despite the clear benefit of exercise on health and longevity, the association between different types of sports and lifespan is yet to be considered. Accordingly, we aimed to study this association in a large international cohort of former athletes using a robust linear regression model. We collected data on athletes from public sources, accumulating a total of 95,210 observations, 95.5% of which were accounted for by males. The dataset represented athletes born between 1862 and 2002 from 183 countries across 44 sports disciplines.

We calculated the change in lifespan by measuring the difference in age between athletes and the corresponding reference populations, while accounting for variations caused by sex, year of death, and country. The results revealed that various sports impacted lifespan differently, with male athletes being more likely to experience benefits from sports than female athletes. Among male athletes, pole vaulting and gymnastics were linked to the highest extension in lifespan (8.4 years and 8.2 years respectively), while volleyball and sumo wrestling were the most negatively associated with lifespan (-5.4 years and -9.8 years respectively). The association between lifespan and popular team sports in males was positive for cricket, rowing, baseball, water polo, Australian rules, hurling, lacrosse, field hockey, minimal for rugby, canoeing and kayaking, basketball, gridiron football, and football (soccer), and negative for handball and volleyball. Racquet sports (i.e., tennis and badminton) exhibited a consistent and positive association in both male and female athletes, as shown by an extended lifespan of up to 5.7 years in males and 2.8 years in females.

Although lacking conclusive evidence, we theorize that the observed results may be attributed to the aerobic and anaerobic characteristics of each sport, with mixed sports yielding the maximum benefits for the lifespan. While results from female athletes should be cautiously interpreted, our study highlights the complex interplay between sports and lifespan and contributes to the growing body of knowledge on the multifaceted relationship between physical activity and human longevity.

Link: https://doi.org/10.1007/s11357-024-01307-9

Stem cells support surrounding tissue by providing a supply of new cells to replace those lost to the Hayflick limit on somatic cell replication. This activity declines with age, and the reduced supply of replacement cells is a major contributing cause of loss of tissue function. For at least some types of stem cell, loss of activity is a response to the aged environment rather than a matter of cell damage or reduced stem cell population size. Here, researchers explore the mechanisms by which stem cell activity declines with age in flies, and find one point of potential intervention that might be influenced to increase stem cell activity in old flies.

During aging, miscellaneous changes occur in tissue stem cells. Tissue stem cells often exhibit two opposite phenotypes: proliferation and exhaustion. Proliferation can lead to dysplasia and tumorigenesis. Stem cell exhaustion is often defined as a decline in stem cell numbers and renewal capacity. Although stem cell quiescence and exhaustion share the same property of suppressed proliferation, they are distinct in a sense that quiescent cells, but not exhausted cells, can proliferate upon receiving stresses. Thus, stem cell exhaustion can be defined as a stress-induced cellular status exhibiting decrease of either the cell number or proliferative capacity, which makes stem cells refractory to stimulation and unable to renew upon receiving additional stresses.

Aging-induced stem cell exhaustion occurs in many types of tissue stem cells in mice, including hematopoietic stem cells, intestinal stem cells (ISCs), skeletal muscle stem cells, and hair follicle stem cells. Stem cell exhaustion can occur due to two mechanisms: (1) replicative stress in response to proliferation and (2) mechanisms independent of cell proliferation. The resulting phenotype, proliferation or exhaustion, likely depends on the tug of war competition between conflicting signals. In Drosophila, ISCs demonstrate a proliferative phenotype during aging. Many studies focused on what is driving aging-induced ISC proliferation and elucidated the mechanisms such as JNK signaling, commensal dysbiosis, epithelial barrier disruption, mitochondrial regulation, and an ABC transporter-mediated folate accumulation. Although PIWI was suggested to suppress Jak-Stat-mediated exhaustion of ISCs, signaling that skews ISCs toward exhaustion during aging is not known. There might be some undiscovered signals that lead cells toward exhaustion.

There are many silent changes in chromatin structures and gene expression that are not necessarily reflected in manifested phenotypes during aging. Here through analyses of chromatin accessibility and gene expression in intestinal progenitor cells during aging, we discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, ced-6 and ci, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of Trl, ced-6, or ci exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.

Link: https://doi.org/10.1016/j.isci.2024.110793

The retina is the only part of the nervous system readily and easily imaged at low cost. It contains layers of delicate structure and microvessels, all of which accumulates visually distinct changes and damage with advancing age and cellular dysfunction. Given the spread, packaging, and standardization of machine learning technologies on the one hand, and the development of an increasing variety of aging clocks to assess biological age on the other, it was only a matter of time before someone (or several someones) applied machine learning to retinal imagery in an attempt to produce a retinal aging clock. As a general rule, any sufficiently complex set of biological data can be used to produce a reasonably effective measure of biological age. The data contained in images of the retina is no exception.

Today's open access review paper provides a concise tour of present efforts to build retinal aging clocks. This part of the field is far less developed than is the case for epigenetic clocks and other omics clocks. Nonetheless, it is interesting, in large part because a view of the retina is in large part a view of the health of capillaries. Capillary density is known to decrease with age in tissues throughout the body, and the retina is one of the few locations in the body where one can obtain a cost-effective assessment of capillary density. Loss of capillaries means a reduced flow of blood into tissues, and consequent issues of many sorts. It may well be one of the more important aspects of degenerative aging.

Estimating biological age from retinal imaging: a scoping review

This study aimed to appraise existing research using retinal photography to develop biological ageing markers. We sought to determine the accuracy of retinal age prediction models, evaluate their ability to reflect age-related parameters and explore their clinical associations. This scoping review identified models which estimate chronological age from retinal images with moderate to high accuracy and identified several age-related associations.

Four models are currently available to estimate biological age from retinal images, all based on deep learning algorithms: 'Retinal Age', 'EyeAge', 'convolutional network-based model', and 'RetiAGE'. 'Retinal Age', 'EyeAge', and 'convolutional network-based model' were trained to predict numerical chronological age from retinal images, while 'RetiAGE' was trained to predict the probability of an individual being older than 65 years.

All models were trained and validated using a single dataset, predominantly comprising Caucasian or Asian populations. To enhance robustness, both 'EyeAge' and 'RetiAGE' underwent additional internal testing on previously unseen images from the training and validation cohort. For model testing and outcome assessment, the UK Biobank was used by three models: 'Retinal Age', 'EyeAge' and 'RetiAGE'. While the four identified models demonstrated comparable accuracy and performance, it is important to highlight inconsistent reporting of performance metrics, with some pertaining to validation performance, and others test performance. Consequently, the generalisability of these models is uncertain, warranting further work to assess their applicability across diverse populations.

Nevertheless, using retinal age models to predict mortality and morbidity carries significant clinical implications. A key finding from selected papers emphasises that accelerated ageing, calculated as retinal age gap (RAG), age acceleration or other indices, consistently correlates with mortality risk across three models. In addition, 'Retinal Age' and 'EyeAge' show associations with cardiovascular disease, while 'Retinal Age' and 'convolutional network-based model' show connections with the risk of diabetic retinopathy in patients with diabetes. These findings highlight the potential of retinal age as an informative tool for quantifying risk of mortality and cardiovascular morbidity. However, no clinical trials have yet explored the utility or feasibility of the models, a crucial aspect for determining their clinical relevance. Furthermore, factors associated with higher RAG, including glycaemic status, central obesity, and metabolic syndrome, suggest that RAG may provide valuable insight into lifestyle habits and traits that accelerate ageing.

TDP-43 is one of the few molecules capable of misfolding and aggregating to produce pathology in the brain. It is a more recently discovered form of proteopathy than the other well-known problem proteins that contribute to neurodegeneration, such as α-synuclein, amyloid-β, and tau. With increased attention given to TDP-43 by the research community, its contribution to the aging of the brain and neurodegenerative conditions is expanding to be broader than first thought. Here, as one example, researchers provide evidence for TDP-43 to be involved in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder that manifests with movement disturbances, psychiatric changes, and cognitive decline. It is caused by an unstable CAG repeat expansion in exon1 of the huntingtin gene (HTT), which is translated to an abnormally long polyglutamine (polyQ) stretch in the HTT protein. The expanded polyQ repeats lead to aggregation of mutant HTT and the selective neuronal cell loss in the striatum, cortex, and other brain regions in HD patients.

Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior.

Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence of the mouse HTT precursor messenger RNA (pre-mRNA), promotes the transport of exon1-intron1 HTT onto the ribosome, resulting in the aberrant generation of exon1 HTT. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.

Link: https://doi.org/10.1111/acel.14325

Chronic inflammation is a feature of aging, driven by a range of mechanisms, and in turn disruptive to tissue structure and function. It might be argued, then, that the regulators of inflammation are likely important in natural variation in human life span, and might be targeted to slow aging. The challenge to date is that the same regulators of inflammation are involved in both the unwanted chronic inflammation of aging and in the necessary short-term inflammation needed to defend against pathogens and coordinate regeneration of injuries. Ways to act upon these regulators to suppress the former without suppressing the latter do not yet exist, and may or may not be very challenging to develop.

This paper presents a novel perspective, amassing substantial evidence that targeting NLRP3 not only converges various aging mechanisms but also exerts regulatory control over them. This unique approach underscores a sophisticated interdependence that is yet to be fully understood. Furthermore, NLRP3 appears to regulate cellular senescence so that its activation does not lead to pyroptosis. This suggests that senescent cells could be a persistent source of IL-1β production, thereby contributing to aging. The significance of NLRP3 in aging is highlighted by studies demonstrating that its knockout endows mice with a phenotype of healthspan and lifespan. Additionally, treatments targeting pathways upstream of NLRP3 have been shown to extend the healthspan of primates and reverse various aging symptoms in humans.

Therefore, NLRP3 is not merely a participant in the aging process but potentially acts as a master regulator. Modulating NLRP3 could significantly alter the health trajectories of individuals experiencing NLRP3-mediated accelerated aging. Since this process is largely driven by autologous components, the term 'auto-aging' is proposed. Further research is essential to understand the role of NLRP3 in accelerated aging entirely and to develop healthspan-extending therapies targeting this key regulator.

A critical question remains: Should interventions aim to completely inhibit NLRP3 activation or selectively target specific activation pathways to maximize health benefits? While there appears to be redundancy among NLRs in defending against pathogen-associated molecular patterns, broad inhibition might increase susceptibility to specific infections by weakening primary defense mechanisms. Additionally, better biomarkers are needed to gauge the impact of such therapies on NLRP3 activity. Assessments often focus on free IL-1β levels in plasma, which are minimal due to neutralization by soluble IL receptors. Alternatives could include measuring total IL-1β or utilizing surrogate markers like IL-6 downstream of IL-1β, which may provide a more accurate reflection of NLRP3-mediated inflammatory status.

Link: https://doi.org/10.3389/fragi.2024.1452453

In recent years, researchers have suggested that gum disease, periodontitis, may contribute to the development of cardiovascular disease and neurodegenerative conditions. Leakage of pathogens and harmful metabolites into the bloodstream at the gums, leading to an increased level of chronic inflammation, has been proposed as the important mechanism. This is a reasonable proposition. There is some debate over the degree of risk, however, and it is always possible that periodontitis risk is just as driven by degenerative aging as is the case for risk of cardiovascular disease and neurodegenerative disease, obscuring the effects of periodontitis on other diseases because they will tend to independently co-occur anyway.

Human data typically only allows the determination of correlations between conditions and mechanisms, not causation. There are some ways forward, however. In today's open access paper, researchers employ a Mendelian randomization strategy in order to try to gain some insight into causation between aging, periodontitis, and cardiovascular disease. The result is generally supportive of the present consensus, meaning that aging contributes to both periodontitis and cardiovascular disease, but periodontitis can also contribute to cardiovascular disease. It doesn't add much to the present discussion on the size of these contributions.

Biological aging mediates the association between periodontitis and cardiovascular disease: results from a national population study and Mendelian randomization analysis

Using the NHANES database, a large GWAS database, and Mendelian randomization (MR) analyses, this study investigated the complex relationship between periodontitis, cardiovascular disease (CVD), and biological aging. The results indicated that periodontitis was a risk factor for CVD and that aging plays a mediating role in this association. Gene-level predictive analysis further confirmed the causal effect of periodontitis on small-vessel stroke and revealed the causal effect of biological aging on periodontitis and specific CVD. Simultaneously, the study found that CVD may exacerbate the progression of biological aging.

We observed that an increase in the degree of periodontitis was associated with an increased risk of CVD. Additionally, MR analysis revealed the potential causal effect of periodontitis on small vessel stroke. A number of epidemiologic studies have suggested a significant positive association between periodontitis and CVD, such as CHD and stroke. The possible mechanisms for this association include the systemic inflammation caused by periodontitis. Patients with periodontitis often have elevated levels of inflammatory markers in the blood, such as c-reactive protein and white blood cell count. These biomarkers play a key role in the pathophysiological mechanism of CVD. On the other hand, pathophysiological studies have revealed the potential role of oral bacteria in the formation of atherosclerosis. In addition, further supporting the pathological link between periodontitis and CVD is the observation of pathological changes similar to CVD, such as the formation of atherosclerotic plaques, in animal experimental models following the induction of periodontitis.

We investigated the relationship between periodontitis, CVD, and aging markers. The results indicated that the progression of periodontitis is significantly associated with biological aging. This suggests that periodontitis may not only affect oral health but accelerate the systemic aging process. The presence of periodontitis may aggravate the aging of organisms and even increase all-cause mortality. These findings provide strong evidence for the important role of periodontitis in the mechanism of systemic aging. Furthermore, biological aging was found to be linked to a higher risk of CVD, which aligned with previous research. Our findings also suggest a potential causal relationship between biological aging and periodontitis, as well as a reciprocal causal effect between aging and CVD. In other words, aging contributes to the development of periodontitis and CVD and can also be a potential consequence of CVD. These results underscore the intricate interplay between periodontitis, CVD, and biological aging.

Telomeres are repeated DNA sequences at the ends of chromosomes. A little of this length is lost with each cell division, one part of the countdown mechanism that limits the number of times a cell can replicate before becoming senescent or undergoing programmed cell death. In stem cells that must continue to produce daughter cells with long telomeres, the enzyme telomerase is active to lengthen telomeres. To the extent that stem cell activity declines with age, average telomere length in tissues becomes shorter and the number of senescent cells increases, as fewer new long-telomere cells are produced. Meanwhile, cancerous cells have undergone mutational changes allowing them to abuse telomerase to bypass the normal replication limit.

The intersection of aging and cancer is a multifaceted issue arising from the interplay between aging processes and cancer development. In fact, aging is linked to a higher frequency of genetic mutations and genomic instability, all of which can predispose cells to malignant transformation. Additionally, the efficiency of DNA repair mechanisms and immune surveillance declines with age, further increasing cancer risk. Chronic inflammation, characteristic of both aging and cancer, creates an environment conducive to cancer initiation, growth, and progression. Addressing the complex relationship between cancer and aging requires a deep understanding of the underlying molecular and cellular processes and a personalized approach to cancer prevention, detection, and treatment.

Recent research has highlighted the significant impact of chronic inflammation on immune aging, showing a strong correlation between inflammation and telomere biology in various major health conditions, including cancer. New evidence suggests that aging is driven by chronic inflammation, which depletes stem cells, disrupts cellular communication, and leads to telomere loss - telomeres being protective "caps" at chromosome ends. To maintain telomere length and protect chromosomes from damage, highly proliferative cell types, such as hematopoietic progenitors and effector leukocytes, use the enzyme telomerase. Telomerase activity is influenced by leukocyte proliferation, persistent inflammation, and the production of reactive oxygen species (ROS). This review focuses on potential interactions between inflammation and telomere biology in cancer development. Understanding the immune system's interplay with telomerase activity could reveal new therapeutic targets for treating cancer and other age-related disorders.

Link: https://doi.org/10.3390/ijms25158542

A number of neurodegenerative conditions have been linked to alterations in the gut microbiome, distinct from those already taking place with age. The balance of microbial populations making up the gut microbiome shifts with age to favor inflammation over production of beneficial metabolites. Researchers here make an effort to characterize gut microbiome changes associated specifically with Parkinson's disease; whether these are indicative of greater inflammation or they touch on other mechanisms that can drive neurodegeneration remains to be determined. In the context of Parkinson's, it is worth noting that evidence suggests that the misfolded α-synuclein that spreads throughout the central nervous system to drive disease progression initially appears in the intestines rather than the brain in a sizeable number of cases.

Parkinson's disease (PD) has been consistently linked to alterations within the gut microbiome. Metagenomic sequencing was used to characterize taxonomic and functional changes to the PD microbiome and to explore their relation to bacterial metabolites and disease progression. Motor and non-motor symptoms were tracked using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and levodopa equivalent dose across ≤5 yearly study visits.

PD-derived stool samples had reduced intermicrobial connectivity and seven differentially abundant species compared to controls. A suite of bacterial functions differed between PD and controls, including depletion of carbohydrate degradation pathways and enrichment of ribosomal genes. Faecalibacterium prausnitzii-specific reads contributed significantly to more than half of all differentially abundant functional terms. A subset of disease-associated functional terms correlated with faster progression of MDS-UPDRS part IV and separated those with slow and fast progression with moderate accuracy. Most PD-associated microbial trends were stronger in those with symmetric motor symptoms.

In conclusion, we provide further evidence that the PD microbiome is characterized by reduced intermicrobial communication and a shift to proteolytic metabolism in lieu of short-chain fatty acid production, and suggest that these microbial alterations may be relevant to disease progression.

Link: https://doi.org/10.1002/mds.29959

The largely crowdfunded Participatory Evaluation of Aging with Rapamycin for Longevity (PEARL) clinical trial was organized by Lifespan.io, the funds raised in 2021. Those of us who advocate for more (and, importantly, more cost-effective) clinical trials of existing low-cost therapies that might at least modestly affect aging hoped for the PEARL trial to be a good example of the way in which one can put together and run a responsible, low-cost clinical trial. A blueprint that others could follow, or a first example of more trials that could be undertaken by organizations such as Lifespan.io. Everything moves very slowly in medicine, and if the PEARL trial is to be the first in a series, it remains the case that all of the necessary activities and enthusiasm leading to that outcome have yet to happen.

Today's open access paper reveals the first results from the PEARL trial. Rapamycin is a calorie restriction mimetic drug capable of upregulating autophagy. As such we should expect it to have approximately similar outcomes on health measures in the short term in mice and humans, but to do little for human life expectancy. One of the more interesting questions is whether rapamycin treatment, or indeed any robustly effective calorie restriction mimetic targeting autophagy, can outperform the benefits of exercise in our species, as it does in mice. One could argue either way, but there is no good way to know for sure other than to conduct clinical trials with enough participants to achieve statistical significance.

Note that the doses used in the PEARL trial are in effect lower than the commonly used anti-aging dose of 5 mg/week. The rapamycin used in the trial was compounded in a way that turns out to have a much lower bioavailability than mass-manufactured pill forms of the drug. Further, it looks to be the case that more of the data would be statistically significant given a larger study population; whoever chooses to follow on with another study of rapamycin as a treatment to slow aging and improve late-life health should probably try for at least twice as many participants.

Safety and efficacy of rapamycin on healthspan metrics after one year: PEARL Trial Results

A total of 115 participants were included in this study, of whom 40 received 5 mg/week of rapamycin, 36 received 10 mg/week of rapamycin, and 39 received placebo. At baseline, all participant groups were comparable across measures of age, sex, height, weight, BMI, and blood safety markers, with the exception of the mean HbA1C, which was lower in the 5 mg group than placebo. Overall, participants were in exceptionally good health at baseline, as evaluated by self-reports of health.

No significant differences in markers of metabolic health, liver, and kidney function, or moderate to severe adverse events in the rapamycin treatment groups were reported compared to placebo after 48 weeks. This is consistent with previous reports that healthy individuals are not likely to experience serious side effects from low dose rapamycin, and suggests that concerns over negative effects of rapamycin stemming from studies of high-dose, daily usage in chronically ill individuals may have limited applicability in the context of rapamycin use for healthy aging. Indeed, we observed more instances of individuals reporting improvements in chronic ailments in the rapamycin treatment groups than in placebo, and more instances reported of worsening ailments in the placebo group compared to treatment groups after 48 weeks. This effect will be important to investigate further in longitudinal follow-up with PEARL participants.

Over the 48 weeks of the study, weekly rapamycin use demonstrated dose-dependent and sex-specific improvements in multiple functional healthspan metrics compared to placebo, including lean tissue mass, bone mineral content, pain (SF-36, WOMAC), social functioning (SF-36), overall quality of life (SF-36), and overall osteoarthritis (WOMAC) score. All statistically significant benefits were observed in participants taking 10 mg rapamycin per week and consistent with preclinical reports of a female-benefit bias in mice, female participants demonstrated significant benefits across all the outcome measures except bone mineral content. Findings from this study that male participants in the 10 mg rapamycin group gained an average of 1.4% bone mineral content (BMC) over 48 weeks and female participants in the 10 mg group gained an average lean tissue mass of 4.5% hold significant promise for rapamycin in reducing risks of age-related disease and mortality.

While this trial extended notably longer than other human trials of rapamycin use for healthy longevity to date, it is likely that even greater effects would be observed with an increased observation period, a broader (specifically higher) range of doses, as well as a larger study cohort. Across all measures in this study, a remarkable level of variability in response was observed for all rapamycin users, regardless of dose. Given our recent work on the variability of rapamycin bioavailability in individuals, we expect that it played a meaningful role in the results observed here, though this trial concluded prior to our findings on bioavailability. Further, we have discovered since the conclusion of this trial that compounded rapamycin is approximately 3.5x less bioavailable than commercially available formulations, suggesting that the 5mg and 10mg rapamycin groups received an average equivalent of 1.4mg and 2.9mg respectively. Although both doses are relatively low, making the observation of benefits in the treatment group more striking, the 10mg rapamycin cohort in this study was more firmly in the range of what is thought to be an optimal longevity dose range for rapamycin.

Microglia and astrocytes tend towards greater reactivity in the aging brain, entering a more inflammatory state. This sustained inflammation is maladaptive and contributes to the development of neurodegenerative conditions. In the research noted here, the data indicates significant differences in the mechanisms that provoke astrocytes versus microglia into reactivity. Other evidence already links microglial inflammation with amyloid-β and tau protein pathology. The earlier stages of Alzheimer's disease may be inflammatory because of the presence of amyloid-β and its effects on microglia, while the later stages have more of the appearance of an accelerating feedback loop between inflammatory signaling and the presence of pathologically altered tau, both of which generate the other.

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available cerebrospinal fluid (CSF) measures of amyloid-β (Aβ), phosphorylated tau(pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic biomarkers (GAP43 and neurogranin).

Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aβ presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aβ+ individuals and postsynaptic biomarkers in cognitively impaired Aβ+ individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.

In conclusion, our findings support a link between glial reactivity and synaptic dysfunction in living humans, which appears to be explained by pathological phosphorylation of tau. While astrocyte reactivity seems to be a partially independent phenomenon leading to synaptic dysfunction in aging and AD, the effects of microglial activation on synaptic function are determined by the emergence of Aβ pathology. These results suggest that synaptic biomarkers hold potential as secondary endpoints for clinical trials targeting glial reactivity in aging and AD.

Link: https://doi.org/10.21203/rs.3.rs-4782732/v1

Neural stem cells produce new neurons in the brain and are critical to memory, learning, and what little capacity for regeneration the brain possesses. Astrocytes are supporting cells that help to maintain the structure and metabolism of brain tissue. Neural stem cells and astrocytes are very similar in lineage and many aspects of their biochemistry. Why are they so functionality different? Given detailed answers to that question, might it be possible to generate more neural stem cells from astrocytes in order to restore lost function in the aging brain with an increased supply of new neurons?

Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions. Thus, how stem cell activity is molecularly encoded remains unknown.

Here we examine the transcriptome, chromatin accessibility, and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, targeting DNA methylation to gain stemness or astrocyte features offers a potential therapeutic avenue to repair the diseased nervous system or fight cancer.

Link: https://doi.org/10.1038/s41586-024-07898-9

Most of the approaches shown to slow aging in laboratory species influence the same underlying mechanisms, meaning the regulation of cell maintenance processes that are activated in response to stresses such as heat, cold, lack of nutrients, and so forth. Arguably the most well studied of these processes is autophagy, a recycling of damaged and excess structures in the cell. This response to stress is fundamental to the evolutionary success of multicellular life, and has existed in more or less its current form for so long that its tendrils sprawl throughout every part of the complex map of cellular biochemistry. Any unbiased search for ways to slow aging will primarily, arguably near entirely, find ways to mimic portions of the response to stress - and researchers have been conducting these searches for decades.

Given a diverse set of apparently unrelated interventions that all turn out to slow aging by affecting different portions of the regulatory system governing stress responses, the next step is to join these dots together. Research of the sort reported in today's open access paper has become commonplace. Here, and in many other cases, researchers find a link between intervention A (in this case rapamycin) and intervention B (in this case spermadine), which leads to a better understand of how the two intervention fit into the regulatory systems governing cell maintenance activities, autophagy in particular.

A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity

Polyamines, including putrescine, spermidine, and spermine, as well as their precursors and regulatory enzymes, are highly conserved across species. Our previous work has highlighted the multifaceted consequences of spermidine supplementation, which exerts cardioprotective and neuroprotective effects, stimulates autophagy and mitochondrial function, and extends lifespan in a variety of laboratory models. These findings are particularly salient given that polyamine metabolism, predominantly regulated by the pacemaker enzyme ODC1 (ornithine decarboxylase 1), is a critical driver of cellular growth. The concordant activity of polyamines, stimulation of cell growth and induction of autophagy, differs from the discordant action of MTOR (mechanistic target of rapamycin kinase), which stimulates cell growth but represses autophagy.

Rapamycin, a potent and selective inhibitor of MTOR, has long been recognized for its ability to extend longevity across species, including yeast and worms. Our recent data demonstrate that rapamycin treatment in yeast is accompanied by a concomitant increase in endogenous spermidine levels. Notably, the inhibition of endogenous spermidine synthesis significantly attenuates the autophagy-inducing and longevity-promoting effects of rapamycin in yeast, human cell lines, and worms, underscoring the essential role of polyamine metabolism in these processes. Accordingly, our study provides further compelling evidence that the pro-autophagic and lifespan-extending effects of dietary restriction and intermittent fasting - physiological triggers that shut down TOR signaling - are largely dependent on functional endogenous polyamine metabolism.

Acute fasting is associated with an increase in polyamine levels across multiple species and tissues, supporting our hypothesis that this rise in polyamines is necessary to trigger the autophagic cascade. Moreover, genetic perturbation of MTOR activity in transgenic mice further corroborates our findings, as changes in spermidine levels align with expected autophagic outcomes. Notably, our previous work has shown that spermidine can effectively counteract the downstream effects of hyperactive insulin-IGF1 signaling during cardiac aging in mice. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.

Transcription factors form one portion of the complex cell nucleus protein machinery that regulates gene expression. One transcription factor typically regulates the expression of many different genes, often largely related to one set of cellular processes. Exploring the biochemistry of transcription factor activity is one way to try to divide the complexity of the cell into different functional areas that are at least a little independent of one another. In exploring the effects of FOXO transcription factors on aging, researchers have found that upregulation of the target gene OSER1 appears to be important in slowing aging. OSER1 is, like klotho, one of the few longevity-associated genes that work in both directions: more of it means a longer life, and less of it means a shorter life.

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan.

In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased mitochondrial ATP production, and altered transcription of mitochondrial genes.

Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.

Link: https://doi.org/10.1038/s41467-024-51542-z

Researchers here use a study of mice with linked circulatory systems to search for factors involved in skin aging. They find that reduced levels of HAPLN1 may be significant in skin aging, as delivery of recombinant HAPLN1 can improve measures of skin aging. The mechanisms of action are hypothesized but remain to be determined. Also remaining to be determined, and unlikely to receive much attention judging by the way this sort of work usually progresses, is the underlying reason why HAPLN1 levels are reduced with age. A molecule by molecule approach to aging doesn't scale: the search for root causes, and efforts to reverse the known root causes of aging, is arguably far more important than a one-by-one focus on the countless consequences of aging.

Heterochronic parabiosis, the parabiotic pairing of two animals of different ages, qualities, or conditions, has been used to provide an experimental system to test the systemic effects of aging, development of age-related diseases, or other age-related parameters. Therefore, we hypothesized that certain systemic factors contribute to the robust regeneration of skin tissues in young animals and inhibit regeneration in old animals. To avoid animal discomfort and mortality owing to parabiosis, the procedure was performed carefully following a precise protocol approved by our animal care committee. To measure changes in the levels of plasma proteins of each parabiont, broad-scale proteomic analysis was performed.

In this study, we demonstrated for the first time that hyaluronan and proteoglycan link protein 1 (HAPLN1, previously known as link protein), whose level of expression decreases in mouse sera with age, played a previously unrecognized function: it restored the amounts of collagen and hyaluronic acid (HA), which progressively declined with skin age. HAPLN1 is a structural protein that links HA and proteoglycans, thus promoting the formation of stable water-rich aggregates in the pericellular matrix (PCM). Our studies suggest that HAPLN1 is a key player that reduces or eliminates cellular damage accumulated in aging skin owing to its involvement in multiple regeneration mechanisms, such as anti-oxidation, anti-senescence, and possibly anti-inflammation. Hence, HAPLN1 substitution therapy could be a promising rejuvenating strategy for preventing or restoring aged skin.

Link: https://doi.org/10.1016/j.matbio.2024.08.009

Even given the point that the mouse models of age-related neurodegenerative conditions are largely very artificial, as mice do not naturally develop any form of pathology that resembles the most common human neurodegenerative conditions, there is compelling evidence for the accumulation of senescent cells in the brain to contribute meaningfully to the onset and progression of these diseases. Cells enter a state of senescence in response to damage, replicative stress, or environmental toxicity, among other causes. In youth such cells serve a useful purpose and are rapidly removed by the immune system. With aging the immune system becomes less efficient and as a result senescent cells linger and accumulate.

Neurodegenerative conditions have a strong inflammatory component, and senescent cells produce inflammatory signaling. The argument for targeting senescent cells to treat neurodegenerative conditions seems a straightforward enough proposition: more senescent cells in the brain means more inflammation and thus a worse prognosis for patients, a more rapid progression of neurodegeneration. Unfortunately, neurodegenerative conditions are not at present at the top of the very long list of conditions that might be treated by selective clearance of senescent cells using senolytic drugs. Academia and industry are largely focused on the role of cellular senescence in the aging of organs other than the brain, and so only the one small, exploratory clinical trial has taken place to test the senolytic combination of dasatinib and quercetin in Alzheimer's disease patients.

Cellular senescence: A novel therapeutic target for central nervous system diseases

Cellular senescence (CS), as a hallmark feature of aging, plays a crucial role in various aging-related diseases, including central nervous system (CNS) disorders. Research findings from cellular or animal disease models, along with detection data from human components, such as cerebrospinal fluid and brain tissue, provide compelling evidence supporting the close correlation between CS and CNS diseases. The transition of critical cellular components in the brain, such as microglia, astrocytes, and brain vascular endothelial cells, toward the senescent phenotype often triggers inflammatory cascades, disrupts the integrity of the blood-brain barrier, impairs neuroregeneration, and contributes to various pathological processes. This exacerbates neural damage, hampers tissue repair, and adversely affects prognosis.

Senescent cells (SCs), besides exhibiting a decline in normal structure and function, are intricately linked to the aberrant generation and accumulation of pathogenic substances, such as β-amyloid (Aβ), Tau protein, and α-Synuclein (α-Syn) in the brain, which contribute to prolonged and complicated conditions. Moreover, SCs can disrupt the balance of the local microenvironment through paracrine mechanisms, amplifying senescent effects and harming surrounding healthy cells. Notably, the development of CNS diseases involves molecular mechanisms that can induce CS. This process exacerbates neurotoxicity in SCs, creating a vicious cycle. Therefore, CS is a promising target for therapeutic intervention in CNS diseases, as disrupting the vicious cycle mediated by SCs in the brain has prospects for preventing and managing such conditions.

Recently, CS has become a prominent area of research in CNS diseases, especially neurodegenerative disorders. Clinical trials on senolytics in CNS disorders are limited. This is primarily because CS-based targeted therapy represents a relatively novel approach, and the diverse complexity of CNS diseases poses challenges in implementing and designing these methods. Further complicating matters is the unique structure of the blood-brain barrier, which limits the entry of many drugs into the brain to exert their effects while avoiding severe adverse effects. Only one study on Alzheimer's disease (AD) (NCT04063124) has published preliminary results. The trial recruited five patients with early AD symptoms for a 12-week intermittent anti-CS treatment (dasatinib and quercetin, D+Q). According to published data, both senolytic components D and Q levels are elevated in the blood. D was detected in the cerebrospinal fluid of four patients, while Q was not in any patient's cerebrospinal fluid. Notably, the team observed an increase in the expression of inflammatory cytokines in the participants' fluid. They speculated that this could be related to a transient trigger of inflammation when SCs are cleared or that it could serve as a marker of SC death.

While this early clinical study established that senolytic therapy is safe, feasible, and well tolerated in AD patients, effectively clearing amyloid-like proteins and reducing blood inflammation, a larger sample size and a placebo control group are required in future studies for further scientific validation. Trials NCT04685590 and NCT04785300 are advancing in this direction. These pioneering efforts to leverage senolytics for treating CNS diseases are highly anticipated.

The gut microbiome changes with age in ways that increase inflammation and reduce the production of beneficial metabolites. Further, the balance of microbial populations is noted to tend towards distinct differences from the norm in patients with certain neurodegenerative conditions. A number of mechanisms by which the gut microbiome can influence the brain are well established, such as via production of butyrate, or the aforementioned increase in disruptive systemic inflammatory signaling. There are likely many more to be discovered as researchers continue to explore the fine details of aging throughout the body.

The human gastrointestinal (GI) tract contains trillions of microorganisms that exist symbiotically with the host due to a tolerant, regulatory cell- rich intestinal immune system. The microbiota-gut-brain axis (MGBA) refers to the interaction between host microbiome, the central nervous system (CNS), and the gastrointestinal tract. Barriers extending beyond the gut epithelial barrier, spanning the MGBA, are emerging as novel pathways facilitating communication between the gut microbiome and the brain. Disruption of the barrier integrity contributes a variety of gastrointestinal and neurological diseases. For decades, our understanding of barriers has shifted from perceiving them as rigidly impermeable cellular structures to dynamic and finely regulated communication interfaces with varying levels of permeability.

In this review, we explore barrier structure and function across the MGBA and examine the modulation of barrier function upon gut microbiota alteration. Additionally, we provide a summary of current knowledge concerning the lymphatic vasculature in the GI tract and CNS, highlighting its role in linking the reciprocal relationship between the lymphatic system and the microbiota, which collectively contributes to whole-body homeostasis. For decades, blood vessels and nerves were thought to be the primary pathways by which metabolites and toxins affect distant organs. It now appears that intestinal lymphatics constitute an additional pathway in the gut-organ axis. Numerous diseases are associated with deranged blood vessel endothelial barrier function, increased permeability, and extravasation into the microenvironment surrounding lymphatic vessels. It is conceivable that the microbiota might exert its effect on the initiation or progression of CNS disease through the lymphatic network in a direct or indirect manner.

Link: https://doi.org/10.1080/19490976.2024.2387800

Parkinson's disease is a synucleinopathy, driven by the pathological biochemistry that surrounds the misfolding, spread, and aggregation of α-synuclein. Here researchers note that aspects of lipid metabolism in the brain likely plays an important role in how α-synuclein causes the dysfunction and death of neurons. This is not a well-studied topic, but given greater interest perhaps might yield novel approaches to therapy.

Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition.

Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing.

Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.

Link: https://doi.org/10.3389/fmolb.2024.1455817

The growing costs of obesity have prompted considerable research and development efforts focused on pharmacological approaches to weight loss. Another possible avenue is to develop drugs to reduce some of the negative impacts of aged and excess fat tissue, such as the chronic inflammatory signaling produced by visceral fat. While it is reasonable to argue that weight loss is the preferential approach for people who are overweight, comprehensive rejuvenation is not yet a reality and older people, even thin older people, undergo poorly understood and incompletely mapped changes in cell biochemistry and immune function that make fat tissue more inflammatory.

Inflammation in fat tissue is a function of the immune system, provoked by the metabolic activity of fat cells. Chronic, unresolved inflammation is harmful to tissue function throughout the body, contributing to the onset and progress of age-related disease. In today's open access paper, researchers discuss a potential regulator of this inflammation. They show that inhibiting the interaction between innate immune cell receptor BLT1 and its binding ligand LTB4 reduces both obesity-related and age-related inflammatory immune cell behavior in fat tissue.

Role for BLT1 in regulating inflammation within adipose tissue immune cells of aged mice

Aging is a complex biological process characterized by obesity and immunosenescence throughout the organism. Immunosenescence involves a decline in immune function and the increase in chronic-low grade inflammation, called inflammaging. Adipose tissue expansion, particularly that of visceral adipose tissue (VAT), is associated with an increase in pro-inflammatory macrophages that play an important role in modulating immune responses and producing inflammatory cytokines. The leukotriene B4 receptor 1 (BLT1) is a regulator of obesity-induced inflammation. Its ligand, LTB4, acts as a chemoattractant for immune cells and induces inflammation. Studies have shown that BLT1 is crucial for cytokine production during lipopolysaccharide (LPS) endotoxemia challenge in younger organisms. However, the expression patterns and function of BLT1 in older organisms remains unknown.

In this study, we investigated BLT1 expression in immune cell subsets within the VAT of aged male and female mice. Moreover, we examined how antagonizing BLT1 signaling could alter the inflammatory response to LPS in aged mice. Our results demonstrate that aged mice exhibit increased adiposity and inflammation, characterized by elevated frequencies of B cells and T cells, along with pro-inflammatory macrophages in VAT. BLT1 expression is the highest in VAT macrophages. LPS and LTB4 treatment result in increased BLT1 in young and aged bone marrow-derived macrophages (BMDMs). However, LTB4 treatment resulted in amplified Il6 from aged, but not young BMDMs. Treatment of aged mice with the BLT1 antagonist, U75302, followed by LPS-induced endotoxemia resulted in an increase in anti-inflammatory macrophages, reduced phosphorylated NFκB and reduced Il6.

In conclusion, this study provides valuable insights into the age- and sex- specific changes in BLT1 expression on immune cell subsets within VAT. This study offers support for the potential of BLT1 in modulating inflammation in aging.

An increase in hydrogen sulfide in tissues has been shown to modestly slow aging in mice, acting on some of the well-studied beneficial pathways and cellular maintenance mechanisms triggered by mild stresses. Here, researchers show that hydrogen sulfide upregulates autophagy in muscle tissue, making it one of many interventions that slow aging via this mechanism. The practice of calorie restriction appears to extend life in short-lived laboratory species largely via improved autophagy, but calorie restriction does not radically extend life in long-lived mammals. Calorie restricted mice may exhibit as much as a 40% longer life span, but calorie restricted humans certainly do not. As a result, researchers do not expect that any other autophagy-based approach will do much to extend human life span.

As individuals age, there is a concomitant decline in the number of muscle fibres and the cross-sectional area of muscle. The decline in mass and function of skeletal muscle in older adults often results in falls, disability and even death. Hydrogen sulfide (H2S) is a gasotransmitter that is produced endogenously in mammals, primarily through enzymatic pathways. H2S directly reacts with oxygen, hydrogen peroxide, and peroxynitrite, thereby reducing cellular oxidative damage. Additionally, it can modify proteins post-translationally through S-sulfhydration, which affects their functionality. Studies have demonstrated that human skeletal muscle expresses a considerable number of H2S-producing enzymes.

H2S has been shown to effectively alleviate muscle atrophy caused by diabetes and obesity. The precise mechanism by which this occurs is not yet fully understood. However, scientists have postulated that it may be related to H2S antioxidant stress, the regulation of mitochondrial energy metabolism, the reduction of apoptosis, and the up-regulation of autophagy. The objective of this study was to investigate whether H2S can enhance the expression and S-sulfhydration of USP5, thereby facilitating the deubiquitination of AMPKα1. Which, in turn, would result in the up-regulation of autophagy, which would contribute to the alleviation of skeletal muscle ageing. We find this to be the case.

Link: https://doi.org/10.1002/jcsm.13560

Taurine is a dietary amino acid. Circulating levels in the bloodstream decline with age, but can be restored by supplementation. Taurine supplementation has been shown to produce improved health and modest life extension in mice, and may act to improve protective cellular antioxidant mechanisms, though other mechanisms are likely involved. Human trials have been less promising, but largely predated modern approaches to measuring biological age, and may have been looking at overly specific measurable biomarkers of oxidative metabolism. Given that taurine is safe and cheap, it is an interesting intervention for self-experimenters, even though we shouldn't expect the effects on health and life span to be large in humans.

Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of the somatosensory barrel cortex, relying on the proper functioning and extensive up regulation of the GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice.

The present research explores two potential interventions, taurine supplementation, and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging. Still, they allow for increased somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.

Link: https://doi.org/10.1038/s41598-024-70261-5

Autophagy is the name given to the collection of processes that recycle damaged and excess proteins and structures in the cell. It encompasses mechanisms by which these recycling targets are first identified, then flagged, and finally transported to a lysosome where they are broken down. Upregulation of autophagy has been demonstrated to improve health and slow aging in a range of laboratory species, using a range of different strategies. Mild stress such as that provided by calorie restriction is known to upregulate autophagy, and many of the approaches discovered to date mimic some aspect of the calorie restriction response. Administration of rapamycin, for example, inhibits mTOR signaling to manipulate nutrient sensing in a favorable way.

In today's open access paper, researchers show that targeted upregulation of autophagy in bone marrow progenitor cell populations in aged mice can improve health very broadly, including reductions in inflammation. The actual intent was to slow the loss of bone mineral density that occurs with age, and the intervention achieves this goal as well. Further, the mice lived longer, but when this outcome occurs as a result of manipulating stress response mechanisms there is good reason to think that the degree of extended life in humans will be much smaller than that demonstrated in mice. Plasticity of longevity in response to low calorie intake is an adaptation to reduce the impact of seasonal famine, so only short-lived species exhibit relatively large changes in life span.

Rejuvenation of BMSCs senescence by pharmacological enhancement of TFEB-mediated autophagy alleviates aged-related bone loss and extends lifespan in middle aged mice

Bone marrow stromal/stem cells (BMSCs) are generally considered as the common progenitors for both osteoblasts and adipocytes in bone marrow, and have been shown to have great potential for clinical application. However, their number and function decline with aging, especially the preferential differentiation of aged BMSCs into adipocytes rather than osteoblasts is reasonably accepted as a leading cause of senile osteoporosis (SOP), which is characterized by increased bone marrow fat accumulation and decreased bone loss. Thus, the balance between osteogenic and adipogenic lineage commitment of BMSCs is essential for bone homeostasis.

Despite the fact that the mechanisms under which the lineage shift occurs in aged BMSCs are not fully clear, accumulated studies have showed that diversity strategies for BMSCs rejuvenation are of benefits for bone quality and even healthspan improvement. For example, modification of transcription factors, epigenetics, and autophagy that enhanced osteogenesis and decreased adipogenesis of BMSCs alleviated SOP in mice. The latest evidence uncovered that premature aging of skeletal stem/progenitor cells caused bone loss. Therefore, it is assumed that stimulation of bone formation by BMSCs rejuvenation in vivo is an effective and attractive strategy for age-associated bone loss.

Transcription factor EB (TFEB) is a key transcriptional regulator of autophagy and lysosomal biogenesis. Emerging discoveries demonstrated that TFEB overexpression promoted longevity and reduced the burden of diseases, holding great promise as a therapeutic strategy for multiple age-associated diseases. Regulation of TFEB has been shown to control the activities of osteoblasts and osteoclasts, the two main cells playing in the coupling of bone remodeling for homeostasis, implying its potential use in osteoporosis prevention. However, little is known about the relationship between TFEB activities and osteoporosis. As precursors of bone lineage cells, BMSCs directly contribute to bone remodeling by differentiating into osteoblasts, but how and to what extend TFEB regulates fate decision of aged BMSCs in bone marrow is still unclear.

In this study, we synthesized a novel small molecule compound (named "CXM102") that could promote autophagy activities in aged BMSCs via enhancement of TFEB nuclear translocation, leading to senescence rejuvenation and bone anabolic effects in middle age mice. Additionally, low dose and long-term administration of CXM102 showed better benefits for healthspan than rapamycin in mice, including extended lifespan, reduced serum levels of inflammation, less lipid droplets and fibrosis in organs. Our results demonstrated that CXM102 could significantly counteract aberrant lineage allocations of aged BMSCs, alleviate osteoporotic bone loss, increase healthspan and longevity of middle age mice.

Phenotypic age is a popular measure of biological age, in part because it is easily calculated using a few commonly available assays conducted on a blood sample. One of the interesting items in this study is the fact that average phenotypic age is somewhat lower than chronological age in a large population of older women. The other is that hormone replacement therapy has only a small effect on phenotypic age. As is the case for all current assessments of biological age, the actual utility of phenotypic age for an individual remains to be determined. Is it actionable, will it accurately reflect the effects of a particular intervention on future life expectancy? These questions do not have satisfactory answers at present.

Among the 117,763 postmenopausal women in the UK Biobank (mean [SD] age, 60.2 [5.4] years), 47,461 (40.3%) had ever used hormone therapy (HT). The mean (SD) phenotypic age of the whole population was 52.1 (7.9) years. Individuals who had ever used HT were older in chronological and phenotypic age and less educated, and they had a lower income, higher exposure to nicotine, more prevalent chronic diseases, and higher proportions of bilateral oophorectomy and hysterectomy than those who never used HT.

In our study, using HT for 4 to 8 years was associated with 0.25 fewer years of biological aging discrepancy. In a previous study, middle-aged adults with 1 major chronic disease were an average of 0.2 years older in phenotypic age than disease-free counterparts. Moreover, each 1-year increment in phenotypic age (adjusted for chronological age) was associated with as much as a 9% higher all-cause and a 20% higher cause-specific mortality risk. Accordingly, the 0.25 years of delayed aging observed in our study could translate to approximately 2.25% decreased risk of all-cause mortality and 5% decreased risk of cause-specific mortality. Therefore, the observed magnitude of associations in our study could be relevant for current clinical practice.

In conclusion, postmenopausal women with historical HT use were biologically younger than those not receiving HT, with a more evident association observed in those with low SES. The biological aging discrepancy mediated the association between HT and decreased mortality. Promoting HT in postmenopausal women could be important for healthy aging.

Link: https://doi.org/10.1001/jamanetworkopen.2024.30839

Reduced expression of SK61 is one downstream consequence of mTOR inhibition, a class of intervention that is demonstrated to slow aging in animal models. Researchers here down that SK61 inhibition reduces liver inflammation, in part by reducing the burden of senescent cells and their pro-inflammatory secretions. This in turn may be an important mechanism by which mTOR inhibition improves late life health.

Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion.

Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.

Link: https://doi.org/10.1038/s43587-024-00695-z

Hyperfunction theories of aging have emerged in recent years from the programmed aging camp, vary considerably, and have yet to settle down into a single consensus hyperfunction theory. Roughly speaking, in this viewpoint aging is the consequence of the inappropriate continued activity or reactivation of developmental programs in adult life. This view of aging does not necessarily stand in opposition to the consensus antagonistic pleiotropy viewpoint, in which aging is the consequence of unrepaired damage that accumulates because selection pressure is too weak in late life for better repair systems to emerge. In some cases hyperfunction is seen as a part of this damage. In others, hyperfunction is seen as the underlying cause of aging, a program, while damage is a secondary consequence.

Today's example of hyperfunction theorizing is one of those that downplays the view of accumulated damage, painting damage as a secondary consequence of the underlying program of aging. The authors makes some practical suggestions regarding the way in which research should progress if hyperfunction is the driving theory: find overactivated and harmful development-associated genes and suppress their activity. Theory drives research strategy, and this is why battles over theories of aging are important. If the wrong approach to theory wins out, research and development will tend to lead to only poorly effective therapies, because those therapies fail to address causes of aging and are instead targeting side-effects of aging.

Consolidating multiple evolutionary theories of ageing suggests a need for new approaches to study genetic contributions to ageing decline

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy.

Long-standing frameworks that ageing is caused by a passive accumulation of molecular damage have been challenged in recent years. The emergence of proposed ageing hallmarks motivated substantial scientific efforts to combat these myriad of molecular perturbations, however, yielding limited success. Understanding if the proposed hallmarks of ageing are causally involved in the physiological decline of organisms, or if they represent mere secondary symptomologies to ageing deterioration, remains an ongoing effort. Indeed, considerable model organism research suggests these traits to be poor predictors of healthy ageing. Thus, whilst features of molecular damage, oxidative stress, and mitochondrial dysfunction are sure to plays important roles in exacerbating healthspan decline, proximate molecular events that underpin the onset of healthspan decline remain largely elusive and difficult to study. Evolutionary theory has long maintained that declines in the force of natural selection after sexual maturity allow the sub-optimal expression and function of fitness-promoting genes in late-life. Thus, genomes have evolved for developmental and reproductive success, not healthy ageing.

This suggests that evolutionary neglect encompasses the proximate cause of ageing onset, yet is unable to elucidate precisely which late-acting (pleiotropic) genes contribute to physiological decline. Identifying the entirety of late-acting hyperfunctional genes will, therefore, allow thorough investigations into optimising their expression levels at the organismal and tissue-specific level at geriatric life stages. We propose that combinations of untargeted multi-omics and late-life healthspan screening of gene-by-gene inhibition is the preferred strategy for studying the roles of hyperfunction in normal physiological ageing.

The brain continually adjusts the networks of synaptic connections between neurons, and cognitive functions such as memory and learning absolutely require this ongoing plasticity of neural networks. With aging synaptic plasticity declines, and this loss of function is an important component of cognitive decline and the development of neurodegenerative conditions. Finding ways to improve this plasticity in an aged brain, and to a greater degree than can be achieved by exercise, is a necessary component of research into the treatment of aging.

Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve.

Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activity-dependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important.

In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity.

Link: https://doi.org/10.3389/fnagi.2024.1428244

A better understanding of how exactly Alzheimer's disease progresses may open the door to more effective early intervention aimed at preventing the condition from occurring. The study noted here adds to the evidence for inflammatory dysfunction of microglia as an important early stage in Alzheimer's disease. A broad range of approaches under development can adjust the behavior of microglia, destroy senescent microglia, or even clear all microglia. The animal data supports efforts to test these approaches in Alzheimer's patients, and particularly in the earliest stages of the condition, prior to symptoms, now that assays exist to detect pre-symptomatic Alzheimer's disease.

Though previous studies of brain samples from Alzheimer's patients have provided insights into molecules involved in the disease, they have not revealed many details about where in the long sequence of events leading to Alzheimer's those genes play a role and which cells are involved at each step of the process. A new analysis required over 400 brains. Within each brain, the researchers collected several thousand cells from a brain region impacted by Alzheimer's and aging. Every cell was then run through single-cell RNA sequencing that gave a readout of the cell's activity and which of its genes were active.

Based on the data, researchers propose that two different types of microglial cells - the immune cells of the brain - begin the process of amyloid and tau accumulation that define Alzheimer's disease. Then after the pathology has accumulated, different cells called astrocytes play a key role in altering electrical connectivity in the brain that leads to cognitive impairment. The cells communicate with each other and bring in additional cell types that lead to a profound disruption in the way the human brain functions.

Link: https://www.cuimc.columbia.edu/news/cellular-community-brain-drives-alzheimers-disease

In heterochronic parabiosis, the circulatory systems of an old mouse and young mouse are surgically joined. It is now well established that this accelerates measures of aging in the young mouse, and reverses measures of aging in the old mouse. This observation has given rise to a rapidly shifting area of research that has evolved in a number of directions over the past twenty years. Competing hypotheses regarding the mechanisms by which sharing blood in this way can impact aging have fallen in and out of favor, but are largely still present in some form - and still competing.

Initially, the focus was on factors present to a larger degree in young blood that may encourage favorable changes in the behavior of aged cells and tissues. GDF-11 was an initial discovery, and remains under clinical development as a mode of therapy. Other factors identified as potentially beneficial include oxytocin. Early approaches to build therapies based on transfusion of plasma from young individuals into old individuals produced poor results in both animal studies and human clinical trials, however.

Over time, the view shifted to harmful factors present to a larger degree in aged blood. Dilution of those factors was seen as the critical point, giving rise to experiments in which diluting blood with saline and albumin in aged individuals appeared to produce benefits in animal studies. Human clinical trials remain a work in progress, and it is yet to be settled as to how useful this approach to therapy will turn out to be - not to mention optimal treatment protocols and duration of benefits from a single treatment. At the end of the day, while clinical applications are under development, it remains to be settled as to exactly why heterochronic parabiosis works to improve function in the older mouse. Which mechanisms are valid, and what is the relative importance of those mechanisms? Research moves slowly.

Aging insights from heterochronic parabiosis models

Heterochronic parabiosis has proven to be a valuable tool to decipher some key circulating molecules involved in the aging process, both promoting and delaying it. In general, circulating factors exchanged during parabiosis may promote or delay cellular senescence and help eliminate senescent cells. Parabiosis also appears to rejuvenate mitochondrial function in several contexts. Parabiosis has also been shown to regulate inflammatory processes, either by promoting them during accelerated aging or by preventing them during induced rejuvenation. Specifically, in the brain, accelerated aging leads to altered intercellular communication and increased DNA damage culminating in genetic instability. In contrast, induced rejuvenation enhances proteostasis and epigenetic modifications. In bone marrow, muscle and liver, stem cell depletion is mitigated during induced rejuvenation. Mitochondrial function is improved in brain, hematopoietic and immune cells, vascular endothelium, and muscle. In addition, macroautophagy plays a crucial role in muscle and kidney rejuvenation. Accumulation of senescent cells in the brain, pancreas, hematopoietic and immune cells, muscle, and VAT is prevented during induced rejuvenation. Chronic inflammation is favored during accelerated aging by parabiosis in the brain, bones, muscles, liver, vascular endothelium, kidneys, eyes, and VAT. In contrast, induced rejuvenation reduces inflammation in these tissues and organs.

Proteins identified as relevant in the aging process through this strategy are poised to be prominent targets, first to better understand this intricate process and then to elucidate strategies to delay the harmful effects of aging, such as various age-related diseases, thus improving our quality of life. Researchers around the world can search for inhibitors for targets that promote aging and activators for those that delay it.

It is important to note that one of the main challenges faced by studies on heterochronic parabiosis is that, in most cases, the conditions used vary significantly. This includes variations in factors such as the sex and age of the animals, their location and cross-linked blood vessels, the length of the cross-linking period, surgical procedures, diet, and exercise capacity, among other variables. Therefore, it would be appropriate to establish a convention where the conditions are the same or as similar as possible in order to enhance reproducibility.

Comparing the benefits of induced rejuvenation with the deleterious effects of accelerated aging is complex, as the changes do not usually occur in opposite directions within the same processes. On the contrary, they often involve changes in the same direction, possibly indicating repair, compensatory mechanisms, or alterations in entirely different processes. Despite this complexity, it would be valuable to find a method to evaluate these effects, possibly using statistical and computational models. Additionally, studies aimed at determining whether the age difference between animals and the duration of their cross-linking lead to significant variations in heterochronic parabiosis outcomes would be particularly insightful.

Also, it should also be noted that most studies focus mainly on circulating proteins, while information on other circulating biomolecules such as DNA, non-coding RNAs, extracellular vesicles, lipids, carbohydrates, and their metabolites is rather limited. Similarly, most research only considers blood cells, despite the fact that other cell types can be transferred. This disparity underscores the need for further research to better understand the roles and mechanisms of these less studied biomolecules and cells in various biological processes.

Exploring the combined dataset of transcriptomic, epigenomic, proteomic, and metabolomic information derived from various tissues and cells in parabiosis experiments has the potential to provide a holistic understanding of the aging process. This integrated approach could unveil intricate molecular mechanisms underlying aging-related changes, providing a comprehensive and structured view of how different biological pathways interact and contribute to aging. However, the analysis of these multidimensional data sets presents significant challenges due to their complexity and the large amount of information they encompass. This complexity is due to the interaction of various molecular processes and the need to integrate data from different omics levels.

There are still many challenges and opportunities to be explored with heterochronic parabiosis. Among them, standardizing protocols to obtain as much information as possible and ensure reproducibility, identifying more specific factors with pharmaceutical potential, defining how transferable the findings are to humans, among many other things. It would be interesting if similar experiments could be carried out in long-lived rodents, such as naked mole rats or blind mole rats, as well as in other mammalian models of aging, such as bats, or in animals that experience a rapid decline in health leading to death, such as boreal quolls during the breeding season. These studies could provide valuable information, especially when compared to findings in mice.

The endoplasmic reticulum is a cell structure associated with ribosomes that aids in protein folding and protein transport, but also has a range of other purposes. It is an important component of the machinery that builds proteins and other molecules in the cell. Like other organelles, the endoplasmic reticulum is subject to the cell maintenance processes of autophagy, in which structures or their component parts are identified as worn, damaged, or excess to requirements, and then broken down and recycled. Preventing this autophagy is known to have negative consequences for other organelles, and researchers here show that this is also true for the endoplasmic reticulum. Much of what is noted in this paper parallels what is known of the relationship between autophagy, aging, and mitochondria, another complex organelle essential to cell function: structural changes with age; shifts in autophagy; changes in function; and the protective role of autophagy.

The endoplasmic reticulum (ER) comprises an array of structurally distinct subdomains, each with characteristic functions. While altered ER-associated processes are linked to age-onset pathogenesis, whether shifts in ER morphology underlie these functional changes is unclear. We report that ER remodeling is a conserved feature of the aging process in models ranging from yeast to C. elegans and mammals. Focusing on C. elegans as an exemplar of metazoan aging, we find that as animals age, ER mass declines in virtually all tissues and ER morphology shifts from rough sheets to tubular ER. The accompanying large-scale shifts in proteomic composition correspond to the ER turning from protein synthesis to lipid metabolism.

To drive this substantial remodeling, ER-phagy is activated early in adulthood, promoting turnover of rough ER in response to rises in luminal protein-folding burden and reduced global protein synthesis. Surprisingly, ER remodeling is a pro-active and protective response during aging, as ER-phagy impairment limits lifespan in yeast and diverse lifespan-extending paradigms promote profound remodeling of ER morphology even in young animals. Altogether our results reveal ER-phagy and ER morphological dynamics as pronounced, underappreciated mechanisms of both normal aging and enhanced longevity.

Link: https://doi.org/10.1101/2024.08.07.607085

Cancers are not as high in the list of major causes of death in our species as one might imagine. In this we differ from laboratory mice, which researchers have fondly referred to as "little cancer factories". Nonetheless, when thinking about the evolution of the mechanisms of aging in any mammalian species, one runs into considerations of the risk of cancer again and again. There is a coin, with regeneration and tissue maintenance on one side and risk of cancer on the other. In long-lived species, evolution has come to a balance between these two sides. In our species a lengthening of life span relative to other primates required a suppression of cancer risk that has given rise to a drawn-out decline in function and increasing burden of cellular senescence.

Human lifespan is shaped by both genetic and environmental exposures and their interaction. To enable precision health, it is essential to understand how genetic variants contribute to earlier death or prolonged survival. In this study, we tested the association of common genetic variants and the burden of rare non-synonymous variants in a survival analysis, using age-at-death (N = 35,551, median age-at-death = 72.4), and last-known-age (N = 358,282, median last-known-age = 71.9), in European ancestry participants of the UK Biobank.

The associations we identified seemed predominantly driven by cancer, likely due to the age range of the cohort. Common variant analysis highlighted three longevity-associated loci: APOE, ZSCAN23, and MUC5B. We identified six genes whose burden of loss-of-function variants is significantly associated with reduced lifespan: TET2, ATM, BRCA2, CKMT1B, BRCA1, and ASXL1. Additionally, in eight genes, the burden of pathogenic missense variants was associated with reduced lifespan: DNMT3A, SF3B1, CHL1, TET2, PTEN, SOX21, TP53, and SRSF2. Most of these genes have previously been linked to oncogenic-related pathways and some are linked to and are known to harbor somatic variants that predispose to clonal hematopoiesis. A direction-agnostic approach additionally identified significant associations with C1orf52, TERT, IDH2, and RLIM, highlighting a link between telomerase function and longevity as well as identifying additional oncogenic genes.

Our results emphasize the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.

Link: https://doi.org/10.1101/2024.07.30.24311226

The research and development communities are not good at prioritizing the evaluation and development of combination therapies. The incentives surrounding intellectual property and demands of regulators can explain much of this, and the rest is due to the primary focus on small molecules as a mode of therapy. Any two given small molecules that are individually useful are very likely to interact to produce an overall negative effect, so little work is directed towards speculatively combining drugs.

In the case of aging, however, an effective treatment must involve a package of various approaches to the repair of the cell and tissue damage that drives aging. We might expect these approaches to be more likely act in synergy. That said, it is clear that altering metabolism to slow aging suffers from the small molecule interaction problem, wherein most drugs and supplements that modestly slow aging on their own interact negatively to modestly accelerate aging. The field must focus more upon repair of damage rather than alteration of metabolism if the vision of synergistic therapies is to be realized.

Targeting multiple hallmarks of mammalian aging with combinations of interventions

Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. The maximum known life extension of mice, resulting from a single intervention, does not exceed 50% (Snell mice with Pit1 knockout or Ames mice with Prop1 knockout). Even in these cases the lifespan of mice is much lower than that of similarly sized mammals with negligible senescence such as the naked mole-rat Heterocephalus glaber, indicating that none of these interventions was sufficient to stop aging. One possible explanation is that even if one underlying cause of aging is countered, the remaining aging processes will still limit the animal's lifespan. Thus, we propose the hypothesis that combination therapies can be more efficient against aging.

Targeting multiple pathways at once can provide synergistic effects that are expected to be greater than the simple sum of independent effects. For example, chemotherapy kills cancer cells leading to proliferation of cancer-targeting T cells. However, some cancers evolve adaptations that suppress this immune response. Checkpoint inhibitors can lift this suppression allowing T cells to be more effective. Several clinical trials have revealed that chemotherapy works better when combined with this form of immunotherapy. Similar examples can be found in the field of aging research. Using the model organism C. elegans researchers have shown that a ribosomal protein S6 kinase beta deletion allele, daf-2 loss-of-function allele and their combined effects increase the worm's lifespan by 20%, 168.8% and 454.4% respectively. A combination of trametinib, rapamycin, and lithium increase the longevity of Drosophila more than each single intervention or pairs of interventions. These drugs inhibit mitogen-activated protein kinase kinase, mTOR complex 1, and glycogen synthase kinase-3 respectively, thus targeting various components of the nutrient-sensing network. Generally, as aging-related pathologies are typically comorbid, targeting multiple biological processes or their separated nodes may be more effective than targeting a single one.

Currently, the most comprehensive analysis of synergistic anti-aging interactions is provided by the SynergyAge database which contains the current state of the art collection of data on long-lived and short-lived genetic mutants with over 1800 gene combinations. However, the database does not cover pharmacological and gene therapy interventions which are arguably more relevant for practical human lifespan extending application. Here we review existing data on combinations of pharmacological and genetic interventions targeting one or many pathological processes described as the hallmarks of aging in mice. While we also discuss studies performed on other mammals, we focus on mice because they were used in the largest number of longevity intervention studies. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.

Studies of the biochemistry of wound healing in species capable of complete regeneration of limbs and organs, such as salamanders and zebrafish, has pointed to differences in the behavior of senescent cells and immune cells such as macrophages during the regenerative process. Senescent cells are created as a result of injury, and cleared soon afterward by immune cells. While they are present, they appear to assist in the processes of regrowth and repair. It is hoped that a sufficient understanding of the biochemistry of proficient regeneration in salamanders and zebrafish will lead to ways to recreate the ability of embryonic mammals to regenerate lost body parts. The capability is clearly there, but lost in adult life.

Zebrafish spontaneously regenerate their retinas in response to damage through the action of Müller glia (MG). Even though MG are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration, with temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging but are still metabolically active, releasing a variety of signaling molecules as part of the senescence-associated secretory phenotype.

Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia /macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.

Link: https://doi.org/10.59368/agingbio.20240021

Older people are less capable of regeneration from injury. On top of that, the heart is one of the least regenerative organs in the body, vulnerable in ways that other muscle tissue is not. Cardiovascular disease leads to heart injury, and the aged body is much less able to compensate than would be the case in a younger individual. These are problems in search of solutions. Even in a world in which the case of cardiovascular disease, the growth of atherosclerotic lesions in blood vessels, is prevented, one would still want to be able to reverse the loss of tissue maintenance and regenerative capacity of the heart.

In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is rare. This is unfortunate as aging induces many changes in the heart. As the heart ages, the capacity of the organ to respond to increased workload decreases. The stress this entails promotes diastolic dysfunction, arrhythmias, and heart failure. These changes to the normal function of the heart ensure that young and aged adults respond differently to cardiac injury.

In young adults, cardiac injury initially induces an inflammatory response whereby neutrophils, M1 macrophages, T-cells, and B-cells invade the injury area to remove dead cells and initiate the reparative phase. The reparative phase is associated with a shift in immune cell populations which actively resolve inflammation and induce fibroblasts to secrete fibrous tissue proteins. The latter results in a stable scar. In contrast, the inflammatory response in older hearts following injury is muted; resulting in delayed clearance of dead cells. Moreover, fibroblast responses to fibrotic cues are markedly weaker. Fibrous protein production is dampened, leading to weaker and less stable scars. Weaker scars affect cardiac function by increasing systolic dysfunction and dilative remodeling. Dampened immune and fibroblast responses in aged individuals lowers the capacity to respond to stressors.

Link: https://doi.org/10.1016/j.jbc.2024.107682

Evidence suggests that improved autophagy is the most important mechanism by which calorie restriction and other mild stresses produce slowed aging and extended life in lower animals and mammals. Disabling autophagy prevents calorie restriction from lengthening life span in laboratory species. Autophagy is the collection of processes responsible for recycling damaged proteins and cell structures. One might think, in a simple model of the situation, that keeping molecular damage to a low ebb over time reduces secondary consequences of that damage and consequent loss of function. We might look at cellular senescence as one of those secondary consequences. Certainly, the evidence suggests that calorie restriction and pharmacological approaches to improve autophagy such as mTOR inhibition reduce the pace at which cells become senescent and thus lowers the harmful burden of senescent cells in older individuals.

The mTOR inhibitor rapamycin and calorie restriction are both modestly better than exercise when it comes to extending life span in short-lived species, which is a decent reason to believe that developing drugs to upregulate autophagy is a worthwhile pursuit. The positive effects of exercise on late life health and life expectancy remain the low bar to beat for academia and industry. Few approaches have managed this to date.

There are two points to consider that make this all somewhat less clear cut, however. Firstly, it is well established that calorie restriction, and other forms of mild stress leading to upregulation of cellular maintenance processes such as autophagy, have diminishing effects on life span as species life span increases. Mice can live up to 40% longer on a low calorie diet. Humans most certainly cannot, and while the actual number is unknown, it seems unlikely that decades of sustained calorie restriction in humans can add more than a few years of life. Why this is the case when the short-term benefits to health and metabolism are quite similar remains a open question.

Secondly, one of the more noteworthy ways in which autophagy cleans up damage in the cell is to recycle worn and damaged mitochondria. Mitochondrially targeted autophagy is known as mitophagy. Every call contains hundreds of mitochondria engaged in the production of chemical energy store molecules, but the mitochondrial population becomes less efficient with age. Evidence points to failing mitophagy, either because autophagic mechanisms in general are faltering, or because changes in mitochondria prevent the efficient application of mitophagy to damaged mitochondria. A whole range of pharmacological approaches to improving mitochondrial function appear likely to produce benefits by improving mitophagy - but none of these appear to improve on the effects of exercise. Drugs and supplements that improve mitophagy, perhaps indirectly by altering mitochondrial dynamics, don't appear to be as good as those that directly upregulate autophagy. That is a bit of a puzzle given the consensus on the importance of mitochondria to aging.

None of these questions are in any way going to slow down an industry that is largely focused on producing small molecule therapies that adjust metabolism for some small benefit. Autophagy and mitophagy are widely appreciated targets, and the industry is biased towards a system in which the primary goal is to find new small molecules for established target mechanisms that are slightly better than the existing small molecules for that target. A meaningful fraction of all drug development funding is directed towards this process - and I'm willing to wager that none of the autophagy-directed portion of this established way forward will much move the needle on human longevity over the next few decades. Aiming for a few extra years seems a waste given the vastly greater potential of other lines of research and development.

Hevolution backs $30.7m Series A to advance mitophagy drug

Hevolution Foundation has joined forces with Dolby Family Ventures to invest in Vandria, a company pioneering mitochondrial therapeutics, with a view to expediting the development of a promising drug designed to improve cognitive function. The total Series A financing now stands at $30.7 million, with Hevolution and Dolby Family Ventures joining ND Capital as institutional backers. This funding is set to facilitate the clinical advancement of Vandria's lead compound, VNA-318, a small molecule mitophagy inducer aimed at treating neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other age-related conditions.

The investment speaks to a growing interest in mitophagy - an essential cellular process that involves the selective removal and recycling of damaged mitochondria. Mitochondria are critical for maintaining cellular health, and their dysfunction is increasingly linked to numerous human pathologies, including neurodegenerative diseases, cardiovascular disorders, and cancers.

"This financing will enable us to progress further in clinical development with runway from the Series A to complete the Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) first-in-man Phase 1 study of VNA-318 and to initiate three parallel Phase 1b/2a efficacy studies in 2025, subject to positive progress in the Phase 1 and regulatory approvals."

Contractile proteins embedded into the cell cytoskeleton enable muscle cells to change shape in response to stimulus from the nervous system. Here researchers explore age-related changes in these proteins in the heart, finding that the balance of what are thought to be the most important contractile proteins shifts to favor a less effective variant. This may be a maladaptive side-effect, however, and not necessarily the important driver of age-related declines in the ability of heart muscle to contract. Testing that proposition in mice would be fairly straightforward; one could use gene therapies or genetic engineering to rebalance contractile protein expression in favor of the more effective variant and see what happens.

The present study demonstrates that the expression of both cardiac contractile and regulatory proteins is altered during aging, and these changes contribute to the contractile deficits that are associated with aging. Our data show that during aging there is a significant increase in the expression of cardiac myosin heavy chain β (β-MyHC) and phosphorylation of both troponin I (TnI) and myosin-binding protein C (MyBP-C). Similar to our results, others have demonstrated an increase in cardiac β-MyHC during aging.

Cardiac myosin heavy chain α (α-MyHC) has been demonstrated to have a ~2-3 fold higher actin-activated ATPase and velocity of actin movement in the motility assay than cardiac β-MyHC. Additionally, in large mammals, cardiac α-MyHC produces an ~2x higher force compared to cardiac β-MyHC, while there is no difference in force for α-MyHC and β-MyHC in smaller mammals including the mouse and rat. Thus, the increase in the expression of β-MyHC in cardiac muscle during aging documented in the present study would be expected to result in a reduction in rate constant of force redevelopment after quick release and restretch (Ktr) and a decrease the rates of sarcomere length (SL) shortening and relaxation of single cardiomyocytes.

Aging is also well known to be associated with an increase in myocyte size and cardiac fibrosis, which is consistent with our results. Further, despite the increase in myocyte size, total MyHC expression did not change, and thus, the number of myosin filaments per myocyte cross-section would decrease and coupled with the increase in cardiac fibrosis would be expected to contribute to the decrease in the maximally Ca2+ activated force/cross-section in 24 months old rats.

Link: https://doi.org/10.14814/phy2.70012

The immune system is enormously complex, and one can subdivide its cell populations near endlessly via many different combinations of characteristics, most commonly the type and amount of cell surface markers. Immune cell populations change in number and behavior with age, but which of these changes are important and which are only side-effects in the age-related decline of function and growing inflammation of the immune system? As an example of the state of present knowledge, one might look at this open access paper, in which the authors review what is known of T helper cells a population of T cells that displays the CD4 surface marker. This population is diverse in function and behavior; it can be further subdivided in many ways. As for the immune system more generally, its contributions to health, disease, and aging are only partially understood.

CD4+T cells play a notable role in immune protection at different stages of life. As individuals age, significant alterations occur in the internal and external milieu of CD4+T cells. These changes encompass reduced naive CD4+T cell (CD4+TN) levels, thymic hypofunction, peripheral mechanism regulation, untimely quiescent withdrawal, and persistent environmental antigen stimulation. The interplay between the in vivo microenvironment and the aging immune system is intricately linked, resulting in a decline in effector CD4+ T cell (CD4+Teff) proliferation capacity, alterations in differentiation patterns, imbalances in the ratio of type 1 T helper cell (Th1) to type 2 T helper cell (Th2), changes in the ratio of type 17 T helper cells (Th17) to regulatory T cells (Treg), among others. Repeated antigenic stimulation, accelerated homeostasis, and delayed clearance lead to impaired mitochondrial respiration, reduced functionality, accumulation of memory subpopulations with autophagy deficits, loss of CD27 and CD28 surface molecule expression, increased production of cytotoxic molecules, and elevated levels of terminally differentiated CD4+T cells (CD4+TEMRA).

Enhancing the function of CD4+T cell phenotype and targeted depletion thereof represents a crucial approach for improving the immune microenvironment in elderly individuals. Future exploration can focus on the mitochondrial dysfunction, metabolic reprogramming, genetic and epigenetic changes, protein homeostasis imbalance, autophagy defects, loss of cellular plasticity, and reduction of T cell receptor (TCR) pool in aging CD4+T cells to clarify the nature of changes in different subtypes of CD4+T cells under immune aging. More attention should be paid to mutual influence and interaction in the process of CD4+T cell aging, which are necessary to reverse both multi-organ senescence and immune senescence. It is evident that CD4+T cells serve as the central hub, not only influencing other immune cell populations but also orchestrating changes within internal subsets and related signaling pathways.

Link: https://doi.org/10.1111/acel.14317