Fight Aging!

Osteoarthritis, involving degeneration of cartilage tissue and underlying bone in joints, is characterized by chronic inflammation in the affected tissues. Unresolved inflammatory signaling is a feature of aging, disruptive to tissue structure and function. In many age-related inflammatory conditions, researchers are investigating the behavior of the innate immune cells call macrophages. Macrophages can switch between states known as polarizations, the most clearly distinguished of which are M1 (inflammatory and aggressive in attacking pathogens) versus M2 (anti-inflammatory and acting to aid regenerative processes). In many inflammation-associated conditions, macrophages appear overly biased towards M1, amplifying inflammation.

Primary osteoarthritis (OA) is a prevalent degenerative joint disease that mostly affects the knee joint. It is a condition that occurs around the world. Because of the aging population and the increase in obesity prevalence, the incidence of primary OA is increasing each year. Joint replacement can completely subside the pain and minimize movement disorders caused by advanced OA, while nonsteroidal drugs and injection of sodium hyaluronate into the joint cavity can only partially relieve the pain; hence, it is critical to search for new methods to treat OA.

Increasing lines of evidence show that primary OA is a chronic inflammatory disorder, with synovial inflammation as the main characteristic. Macrophages, as one of the immune cells, can be polarized to produce M1 (proinflammatory) and M2 (anti-inflammatory) types during synovial inflammation in OA. Following polarization, macrophages do not come in direct contact with chondrocytes; however, they affect chondrocyte metabolism through paracrine production of a significant quantity of inflammatory cytokines, matrix metalloproteinases, and growth factors and thus participate in inducing joint pain, cartilage injury, angiogenesis, and osteophyte formation.

The main pathways that influence the polarization of macrophages are the Toll-like receptor and NF-κB pathways. The study of how macrophage polarization affects OA disease progression has gradually become one of the approaches to prevent and treat OA. Experimental studies have found that the treatment of macrophage polarization in primary OA can effectively relieve synovial inflammation and reduce cartilage damage. The present article summarizes the influence of inflammatory factors secreted by macrophages after polarization on OA disease progression, the main signaling pathways that induce macrophage differentiation, and the role of different polarized types of macrophages in OA; thus, providing a reference for preventing and treating primary OA.

Link: https://doi.org/10.1186/s13018-024-05052-9

The common age-related degenerative conditions that affect muscle and bone are driven in part by the accumulation of senescent cells that takes place throughout the body with age. Senescent cells are created constantly throughout life, largely as a result of cells reaching the Hayflick limit on replication, but also due to forms of damage. In youth, these cells are cleared rapidly by the immune system, but this clearance falters with age allowing a population of lingering senescent cells to accumulate. These cells secrete pro-inflammatory, disruptive signals that degrade tissue structure and function.

Osteoporosis, sarcopenia, and osteoarthritis, three common musculoskeletal disorders that often coexist in the elderly population. The loss of bone and muscle mass and the progressive degradation of cartilage are the macroscopic effects of the complex pathological processes underlying these diseases, in association with an increased susceptibility to fractures and an elevated risk of falls. From a microscopic point of view, affected tissues are characterized by numerous cellular and molecular alterations that induce a state of replicative senescence, irreversibly compromising the quality of the musculoskeletal system. Not surprisingly, cellular senescence has recently emerged as a critical element in the pathophysiology of osteoporosis, sarcopenia, and osteoarthritis, highlighting the need for further studies to understand the intricate relationship between cellular senescence and musculoskeletal functions, as well as to develop effective strategies to mitigate and manage these debilitating conditions.

Cellular senescence has been suggested to be among the mechanisms responsible for the decline in regenerative function observed in muscle and bone stem cells with advancing age because of the up-regulation of certain proteins, including p16, p21, and p27, responsible for altered tissue metabolism. Particularly, senescent bone cells are known to release the senescence-associated secretory phenotype (SASP) that promotes osteoclast activity, inducing bone resorption and accelerating bone mass loss. In agreement, studies in mouse models have shown that the elimination of senescent cells improves bone mineral density and bone microarchitecture, counteracting the onset of osteoporosis. Furthermore, in skeletal muscle, the senescence of satellite cells, which are essential for muscle regeneration, significantly reduces tissue repair capacity. In this regard, experiments in mouse models have shown that the elimination of senescent cells improves muscle function and increases muscle mass, suggesting senolytics as potential strategies in the treatment of sarcopenia. Finally, the accumulation of senescent cells in joints has been suggested to contribute to cartilage degradation and synovial inflammation, exacerbating the joint deterioration that characterizes osteoarthritis.

Link: https://doi.org/10.3390/biomedicines12091948

The information of the mind is encoded in physical structures in the brain, with some debate over exactly which physical structures. Survival after cold water drowning is one example to demonstrate that all electrical activity in the brain can cease without erasing the mind. Therefore memory and all other aspects of the function of the mind must be recorded as physical structures. Given that this is the case, death does not have to be the end. If the brain is preserved sufficiently well at low temperature, then one can be dead but not gone. There is some greater than zero chance of restoration to life in an era of greater technological capabilities than ours.

A growing community feels that sizable gains in life expectancy, and rejuvenation therapies capable of adding significant life expectancy for old people, will be slow in arriving from the biotechnology community. Therefore, there must be a greater focus on improving present approaches to the cryopreservation of patients immediately following death, expanding the presently small cryopreservation industry, and offering some alternative to the grave and oblivion. A part of this effort is to publish and advocate; the path to improvement is actually quite clear. Indeed, the much longer path to producing technologies capable of restoring a cryopreserved individual is also quite clear. The technological capabilities needed can be clearly envisaged and enumerated, and have been.

Biostasis: A Roadmap for Research in Preservation and Potential Revival of Humans

Biostasis is the practice of preservation of humans for the long-term with the intent of future recovery, if this ever becomes feasible. Biostasis can be distinguished into two hypothetical modalities: (a) provably reversible preservation and (b) preservation of informational features in the body in a way that is not reversible with currently known technologies, with the hope that such technologies can be developed and implemented in the future. Provably reversible preservation, also known as suspended animation, is not yet possible for humans, and probably will not be possible anytime soon, absent incredibly rapid advances in preservation technology. Yet, contemporary biostasis methods do not need to be proved to be reversible now in order to allow for a potential chance at revival in the future. The primary justification of contemporary biostasis, which we adopt here, is the preservation of the brain, which most consider to be the seat of our memories, personalities, and identities. By preserving the information contained within the structures of the brain, we may one day be able to revive the individual using advanced future technologies, even though this would require society to bootstrap the development of those technologies while individuals remain under preservation. This practice is also called neural biostasis, brain preservation, or brain archiving. We use the more general term biostasis in this roadmap.

This roadmap is divided into seven main categories: pre-cardiac arrest factors, post-cardiac arrest stabilization, preservation compounds, preservation procedures, methods for measuring preservation quality, long-term preservation, and restoration and recovery. We have attempted to outline the current state of research and future directions for the field of biostasis, with a focus on the scientific and technical aspects of brain preservation for potential future revival. This roadmap touches on several directions, including the development of better chemical compounds and better delivery approaches for those chemicals. Continued research into platforms and chemicals that could improve neural tissue preservation, alongside research into surgical techniques, cannulation methods, perfusion parameters, and long-term storage methods, would all be enormously valuable.

Economic factors are crucial for any field of scientific research, and biostasis research is no exception. So far, funding for biostasis research has predominantly come from individuals and organizations with a vested interest in the field, such as cryonics companies and individual cryonicists. While this has allowed for some progress, the limited resources have constrained the scope and pace of research. To the best of our knowledge, there has never been specific funding awarded for biostasis research from any government agency. We believe that for the field to grow and reach its full potential, there is a need for funding from larger sources, such as government agencies, academic institutions, and philanthropic organizations without a specific focus on biostasis. However, this expansion of funding sources faces a significant challenge: many potential funders and members of the public are highly skeptical about the feasibility of biostasis. This creates a chicken-and-egg problem, where the field receives little funding because many people do not believe it is promising, but there has also been insufficient research to thoroughly investigate its potential.

Breaking this cycle will likely require innovative approaches to both research and public engagement. Possible strategies to address this include: (1) fostering collaborations between biostasis researchers and mainstream cryobiology or neuroscience labs to increase access to resources and the reliability of the research, (2) developing clearer roadmaps and milestones to demonstrate progress and potential, (3) engaging in more public outreach to address misconceptions and discuss ethical concerns, (4) exploring alternative funding models such as crowdfunding or decentralized science initiatives, and (5) leveraging funding for other research topics where synergies with problems relevant to biostasis exist and publishing resulting findings in reputable scientific journals. Additionally, emphasizing the potential spillover benefits of biostasis research to other fields, such as organ preservation for transplantation, treatment of acute brain injuries, or connectomics, could help attract broader interest and support. Overcoming these funding challenges will be critical for performing a thorough and objective examination of the true potential of biostasis technologies.

Researchers here discuss a well known problem in mouse studies of aging, the inconsistency in outcomes for many of the modestly age-slowing interventions tested to date. The high cost of life span studies means that there are fewer attempts to replicate results than would be desired, and study sizes tend to be smaller than desired. Researchers have pointed out that differences between studies in the setup of control groups may be a sizable part of the problem, and the authors of this paper agree.

Although lifespan extension remains the gold standard for assessing interventions proposed to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that short lifespans in the control group exaggerate the relative efficacy of putative longevity interventions. Due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups.

Incorporating many of these suggestions for optimal mouse husbandry and avoiding pitfalls of other lifespan studies, the rigorous National Institute of Aging Interventions Testing Program (ITP) has become a gold-standard for mouse longevity studies. In the ITP, studies are performed on both sexes, with large sample sizes and across three different centers to address idiosyncratic issues of mouse husbandry. Furthermore, the UM-HET3 mice used by the ITP are relatively long-lived compared to most inbred strains and genetically heterogenous, thereby reducing the likelihood that mice die of strain-specific pathologies, a factor that may confound lifespan data.

A majority of compounds tested by the ITP have not been previously published to extend lifespan in mice, thus we lack a "ground truth" for their expected effect size. Notably, however, the ITP has failed to replicate published lifespan extension for several compounds such as metformin, resveratrol, and nicotinamide riboside, raising concerns about the robustness of published mouse longevity data. Although differences in genetic background, age of treatment onset, husbandry, and dosing between the original study and the ITP cohorts may explain replication failures, another potential factor is methodological rigor.

In this manuscript, we reanalyze data from caloric restriction (CR) studies performed in multiple species, the ITP and other large mouse lifespan studies with a particular focus on control lifespan as one potential explanation for inflated effect sizes and lack of replicability. As a solution, we emphasize the importance of long-lived controls in mouse studies which should reach a median lifespan of around 900 ±50 days, or the comparison to appropriate historical controls, and we term this the "900-day rule".

Link: https://doi.org/10.1016/j.arr.2024.102512

Researchers here provide evidence for autophagy in astrocytes, a large supporting cell population in brain tissue, to be important in determining amyloid-β plaque burden in the aging brain. Autophagy is a recycling mechanism capable of breaking down unwanted proteins and structures. Astrocytes increase autophagic activity in the presence of the amyloid-β protein aggregates (plaques) characteristic of Alzheimer's disease, and in a mouse model that exhibits these plaques the degree of autophagy appears to determine the degree to which problematic amyloid-β is cleared from brain tissue.

Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer's disease (AD). We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of an animal model of AD.

Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of the LC3B gene and turns on a prolonged transcription of the SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal markers and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.

Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

Link: https://doi.org/10.1186/s13024-024-00740-w

A broad array of epidemiological evidence indicates that greater time spent being sedentary and inactive harms long-term health and increases mortality risk. Equally, a similar body of evidence indicates that greater physical activity has the opposite effect, at least up to a point that is far above the level of activity that most people undertake in their day to day lives. When looking at any specific aspect of age-related disease and functional decline, one might expect to find the same patterns, and indeed there are any number of studies in which this is the case.

Today's open access paper considers sedentary behavior and physical activity in the context of white matter hyperintensities, areas of damage in the brain produced by rupture of capillaries and related vascular issues. People accumulate these lesions as they age, each one unnoticed when it happens, but this damage accumulates to harm the function of the brain. As one might expect, more activity correlates with less of this damage to the brain, and the researchers speculate on the usual suspects when it comes to underlying mechanisms.

Associations between accelerometer-derived sedentary behavior and physical activity with white matter hyperintensities in middle-aged to older adults

White matter hyperintensity (WMH) volume measured with magnetic resonance imaging (MRI) serves as a significant indicator of the extent of cerebral white matter lesions, typically associated with ischemia due to small vessel disease. WMHs are frequently found in older cognitively unimpaired individuals, are linked with worse cognitive performance, particularly executive functions and processing speed, are associated with genetic risk of neurodegenerative disease, and can potentially impact both the onset and advancement of dementia related to both Alzheimer's disease (AD) and cerebrovascular disease (CVD). Here, we examine the potential associations of physical activity (PA) and sedentary behaviors (SBs), two modifiable lifestyle factors, with WMH volumes in middle-aged to older adults. In the UK Biobank, we found associations of both moderate-to-vigorous physical activity (MVPA) and SB with WMH volume, and the associations are not fully independent of each other.

A large number of studies have shown that engaging in greater amounts of MVPA is associated with improved vascular health and that SB is associated with vascular pathology and chronic disease. One potential vascular mechanism that could underlie these results is that MVPA may increase cerebral blood flow, which in turn may help prevent the development of high WMH loads. SB, on the other hand, has been linked with reduced cerebral blood flow which may lead to increased lesion load, though this finding has not been consistently replicated.

Our results also align with the growing body of literature emphasizing the synergistic effects of higher PA and reduced SB on various health outcomes. While previous studies have independently linked excessive SB and lack of MVPA with adverse brain health, our study demonstrates how these behaviors interact in their associations with WMH volumes. It is possible that the mechanisms linking PA and SB with WMH volumes may only partially overlap. For example, while both SB and MVPA have been linked with cerebral blood flow and vascular health in previous work, MVPA is also associated with the upregulation of neurotrophic factors (eg, Brain Derived Neurotrophic Factor or BDNF) that may provide additional compensatory protection against the impact of increased WMH volumes.

While our study was not designed to determine whether mechanistic pathways are fully or partially independent, the interactions found here suggest more work is needed to better understand how these two lifestyle behaviors may differentially impact brain lesion loads that may, in turn, influence the risk for cognitive decline and dementia related to both AD and CVD. Overall, our results highlight the importance of considering interactions between these key modifiable behaviors when examining their associations with brain health outcomes.

There is evidence for some stem cell populations to decline in function with age in part because of the aging of the surrounding stem cell niche, detrimental changes in the supporting cells making up the niche. The situation appears similar for oocytes, female germline cells. Their niche is the ovarian follicle, and researchers here show that aged oocytes undergo some degree of functional rejuvenation when placed into an environment that mimics the young ovarian follicle, at least as measured by metrics such as epigenetic profile and mitochondrial function.

An ovarian follicle is a basic functional unit in the mammalian ovary, composed of somatic cells (granulosa cells) that surround and support an oocyte (an immature egg cell) as it grows and matures before ovulation. The granulosa cells communicate with the oocyte to provide essential nutrients and components through channels known as transzonal projections. In turn, the oocyte provides key components that signal the growth and development of granulosa cells. Researchers tapped on this understanding of the relationship between somatic cells of the ovarian follicle and the oocyte to create hybrid ovarian follicles through an ex-vivo 3D culturing platform, building upon previous methods. The team then extracted the oocyte from its original follicular environment and transplanted it to a new follicular environment, whose own oocyte had been removed, to construct the hybrid ovarian follicle.

The researchers confirmed that aged granulosa cells, compared to young granulosa cells, exhibited an increase in the hallmarks of ageing, such as an increase in indicators of DNA damage and other factors linked to programmed cell death. They showed that this aged follicular environment can reduce the quality and developmental potential of a young oocyte.

The research team then created hybrid ovarian follicles containing an aged oocyte (i.e. an immature egg cell from an aged follicular environment) in a young follicular environment. The researchers demonstrated that the quality and developmental competence of the aged oocyte can be substantially, though not fully, restored through "nurturing" in a young follicular environment. The team found that the restoration of the quality of the aged oocyte was attributed to the reshaping of its metabolism and gene expression. The researchers discovered that the young granulosa cells, which were much better at establishing transzonal projections toward the aged oocyte, helped to facilitate this restoration. In addition, there was an improvement in the function and health of oocyte mitochondria, crucial organelles for energy production and cellular metabolism.

Link: https://news.nus.edu.sg/novel-approach-to-rejuvenate-aged-egg-cells/

Periodontitis, gum disease, is thought to contribute to a range of age-related conditions by allowing bacteria and bacterial products into the blood stream to provoke chronic inflammation. The risk of periodontitis is affected by the composition of the oral microbiome. Here, researchers show that the presence of some bacterial species is also correlated with risk of head and neck cancer. Chronic inflammation tends to produce a more hospitable environment for the growth of cancerous tissue.

Experts have long observed that those with poor oral health are statistically more vulnerable than those with healthier mouths to head and neck squamous cell carcinoma (HNSCC), a group that includes the most common cancers of the mouth and throat. While small studies have tied some bacteria in these regions (the oral microbiome) to the cancers, the exact bacterial types most involved had until now remained unclear.

Researchers analyzed data from three ongoing investigations tracking 159,840 Americans from across the country to better understand how diet, lifestyle, medical history, and many other factors are involved in cancer. Shortly after enrolling, participants rinsed with mouthwash, providing saliva samples that preserved the numbers and species of microbes for testing. Researchers then followed up for roughly 10 to 15 years to record any presence of tumors. The investigators analyzed bacterial and fungal DNA from the saliva samples. Then, they identified 236 patients who were diagnosed with HNSCC and compared the DNA of their oral microbes with that of 458 randomly selected study subjects who had remained cancer-free.

Of the hundreds of different bacteria that are routinely found in the mouth, 13 species were shown to either raise or lower risk of HNSCC. Overall, this group was linked to a 30% greater likelihood of developing the cancers. In combination with five other species that are often seen in gum disease, the overall risk was increased by 50%. This is the largest and most detailed analysis of its kind to date. It is also among the first to examine whether common fungi, organisms like yeast and mold that, along with bacteria, make up the oral microbiome, might play a role in HNSCC. The new experiments found no such role for fungal organisms.

Link: https://nyulangone.org/news/bacteria-involved-gum-disease-linked-increased-risk-head-neck-cancer

Autophagy and the ubiquitin-proteosome system (UPS) serve similar purposes in the cell. Both flag unwanted materials in the cell for recycling, and then break them down into raw materials for further protein synthesis. In the case of autophagy, materials are wrapped in an autophagosome membrane and then conveyed to a lysosome that dismantles structures and proteins using the enzymes that it contains. In the case of the UPS, ubiquitination of a protein allows that protein to enter a proteasome, the interior of which breaks it apart.

Both of these processes are used to remove excess and damaged molecules that may harm a cell. Up to a point, greater activity of these maintenance processes produces healthier, more resilient cells. Repeated across the entire organism, this leads to a slowing of degenerative aging. A number of approaches have been shown to upregulate autophagy. Fewer improve proteasomal function. In today's research materials, scientists report on an approach that improves both, and demonstrate slowed aging in flies as a result.

Scientists investigate a potential anti-aging drug that could preserve proteasomes and autophagy systems

Proteasomes are protein complexes that break down faulty proteins into smaller peptides. On the other hand, autophagy is a process by which cells degrade and recycle larger structures, including protein aggregates, through the formation of specialized vesicles. Both systems work in concert to maintain proteostasis, but the mechanism of their synergistic activation to mitigate the effects of aging is not well understood. "A few years ago, I learned from an academic conference that a certain drug called IU1 can enhance proteasomal activity, which encouraged our group to test its anti-aging effects."

The researchers employed an animal model for studying the aging process: fruit flies from the genus Drosophila. Since fruit flies have a short lifespan and their age-related muscle deterioration is quite similar to that in humans, Drosophila constitutes a valuable model for studying aging. They treated flies with the drug IU1 and measured various behavioral and proteostasis-related parameters. "Inhibiting the activity of ubiquitin specific peptidase 14 (USP14), a component of the proteasome complex, with IU1 enhanced not only proteasome activity but also autophagy activity simultaneously. We demonstrated that this synergistic mechanism could improve age-related muscle weakness in fruit flies and extend their lifespan."

Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging.

Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.

A number of studies have indicated that poor sleep quality negatively impacts long term health. This analysis suggests that the correlation between poor sleep quality and increased mortality is mediated by other factors such as weight and chronic illness. In other words that underlying causes lead to both reduced sleep quality and increased mortality risk. If looking to improve long-term health, a focus on sleep may not be the right place to start for most people.

Inadequate sleep duration and poor sleep quality are becoming significant public health issues linked to cardiometabolic risk factors like obesity, particularly with an aging population. Approximately 20% of adults are impacted by health issues associated with substandard sleep quality or insufficient sleep durations. Research has demonstrated that the occurrence of dementia is indicative of a greater risk of future all-cause mortality . Furthermore, there is increasing evidence suggesting that both short and lengthy sleep durations, as well as other disturbances, are associated with higher risks of mortality from all causes. Limited attempts to assess the connection between sleep and neurodegenerative illnesses usually found that insufficient sleep length, low sleep quality, and sleep disorders were associated with negative outcomes that included dementia.

Considering the interconnection between sleep, dementia, and the rate of mortality, it is important to investigate the pathways and potential interactions among them. This study aims to investigate the relationship between poor sleep quality and dementia status with mortality risk. We examine this relationship independently of potential confounding factors, while also considering the influence of sex and race. The study is conducted using a sub-sample of the Health and Retirement Study (HRS) with complete algorithmically defined dementia status and probability outcomes. The participants in this sub-sample have a mean age of approximately 78 years. Furthermore, we conduct a simultaneous examination to assess the potential interaction between poor sleep quality and dementia outcomes in determining the risk of mortality.

Poor sleep quality was only directly related to mortality risk before adjustment for lifestyle and health-related factors. Therefore, the potential causal effect of poor sleep quality on mortality risk appears to be confounded by other lifestyle and health-related factors. Dementia was positively associated with mortality risk, particularly among individuals with better sleep quality and among males.

Link: https://doi.org/10.18632/aging.206102

Researchers here investigate a less commonly discussed aspect of Parkinson's disease, which is that patients reliably exhibit reduced uric acid levels in serum and cerebrospinal fluid. Present explanations for this phenomenon remain insufficient, and further research is needed to (a) understand why this happens and (b) whether pulling further on this thread could lead to useful therapies that can slow the progression of Parkinson's.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Despite the undetermined pathogenesis of PD, serum uric acid (UA) levels are decreased in patients with PD. A meta-analysis of dose-response studies established a correlation between a 6% increased risk of PD and every 1 mg/dL decrement in serum UA level. Although there is evidence of decreased UA levels in patients with PD, the causal relationship between UA levels and PD onset or progression remains unclear. Findings suggest that the reduction in serum UA levels in PD is not a causative factor in the onset or progression of the disease but rather a consequence of impaired mitochondrial function, altered gastrointestinal function, and impaired motor function, which may also influence the onset and progression of PD (reverse causation).

Alterations in purine metabolism are also key to understanding the pathophysiology behind lower UA levels in PD patients. UA production follows this pathway: inosine monophosphate (IMP) → inosine → hypoxanthine → xanthine → UA. Although the levels of inosine, hypoxanthine, and xanthine, which are "upstream" in the purine metabolic pathway, may affect UA levels, the "downstream" product in patients with PD, no past studies have explored upstream purine metabolism in the CSF and blood of patients with PD.

Our study compared serum and cerebrospinal fluid (CSF) levels of inosine, hypoxanthine, xanthine, and UA in PD patients and healthy controls. We analyzed 132 samples using liquid chromatography-tandem mass spectrometry. Results showed significantly lower serum and CSF UA levels in PD patients than in controls. Decreased serum hypoxanthine levels were observed in PD patients compared to controls with decreased CSF inosine and hypoxanthine levels. Our findings suggest that decreased UA levels in PD patients are influenced by factors beyond purine metabolism, including external factors such as sex, weight, and age. The observed reductions in serum and CSF hypoxanthine and CSF inosine highlight potential impairments in purine recycling pathways, warranting further research into alternative therapeutic strategies.

Link: https://doi.org/10.1038/s41531-024-00785-0

While considering your end of year charitable donations for 2024, why not get in early and donate to support mouse studies of multiple combined rejuvenation therapies presently underway at Longevity Escape Velocity (LEV) Foundation? Up to EUR 200,000 ($220,000 or so) of donations to the LEV Foundation will be matched during October, so donating now will bring greater funding to the table than donating later.

Donations from Didier Coeurnelle enable next phase of Robust Mouse Rejuvenation research program

Longevity Escape Velocity Foundation (LEVF) today welcomes two very generous donations from long-time supporter of longevity research and activism, Didier Coeurnelle. The first donation is 200,000 euros (approximately 220,000 US dollars). The second donation, of up to another 200,000 euros, is dependent on LEVF receiving matching gifts from other donors from 1st October until the end of the month (October 31st). These donations enable a key set of pre-study pilots ahead of the next phase of LEVF's groundbreaking investigations into the effects of combining different damage-repair interventions for middle-aged mice.

Longevity Escape Velocity (LEV) Foundation exists to conduct and inspire research to proactively identify and address the most challenging obstacles on the path to the widespread availability of comprehensively effective treatments to cure and prevent human age-related disease. Donations are processed free of charge by Every.org, a 501(c)3 non-profit, which will issue a tax receipt to you and disburse the full value of your gift (excluding only any applicable third-party fees) to us. Our partnership with Every.org markedly reduces administrative and regulatory overheads related to donations, enabling us to focus solely on realizing our mission.

A primary focus of LEV Foundation's work is to empirically demonstrate the feasibility and value of the divide-and-conquer approach to treating age-related disease - that is, the simultaneous deployment of therapies that independently address the distinct classes of damage that accumulate in aging bodies. In partnership with Ichor Life Sciences, we'll be conducting large-scale mouse lifespan studies of such therapeutic mixtures. To ensure the results of these studies are rapidly translatable to humans already in middle and old age, this program will focus solely on late-onset interventions. We anticipate that this program will deliver dramatic results both in scientific terms, and in illustrating to the general public the extraordinary potential of comprehensive rejuvenation medicine.

Why support the LEV Foundation? Because too few research organizations are working on combination therapies for the treatment of aging. Brian Kennedy's lab has demonstrated that combining small molecules that alter metabolism to modestly slow aging is a poor way forward: combine two mildly effective molecules and the result is as likely to be modestly accelerated aging as it is to be synergy in slowing aging. But what if one combines therapies that act on aging via repair of the known forms of cell and tissue damage that cause aging? These seem much more likely to exhibit synergies in improving health and extending life span. Fixing two problems should be better than fixing one, and the development of senolytic drugs to clear senescent cells has demonstrated in animal studies that fixing one problem can be pretty good for health and longevity.

But is anyone testing the available approaches to damage repair in combination? Not really, other than the LEV Foundation mouse studies. The obvious next step after developing a range of rejuvenation therapies that each address a single form of damage is to combine them, but even though this was always understood to be the obvious next step, it has been given little thought in research circles. Developing a better understanding of where the major challenges and benefits stand in the combination of approaches to rejuvenation is overdue, and a useful project.

Researchers here report on a novel omics analysis of changes in cell biochemistry produced by various approaches to slowing or reversing aspects of aging, giving rise to what they call a cell rejuvenation atlas. The researchers used their atlas to improve the understanding of how a few of the many regulators of cell behavior produce benefits in the context of aging, and suggest that this approach may yield further insights into targets for drug development to at least slow the progression of aging.

Current rejuvenation strategies, which range from calorie restriction to in vivo partial reprogramming, only improve a few specific cellular processes. In addition, the molecular mechanisms underlying these approaches are largely unknown, which hinders the design of more holistic cellular rejuvenation strategies. To address this issue, we developed SINGULAR (Single-cell RNA-seq Investigation of Rejuvenation Agents and Longevity), a cell rejuvenation atlas that provides a unified systems biology analysis of diverse rejuvenation strategies across multiple organs at single-cell resolution. In particular, we leverage network biology approaches to characterize and compare the effects of each strategy at the level of intracellular signaling, cell-cell communication, and transcriptional regulation.

Our approach successfully identified several previously known age-related transcription factors (TFs). For instance, we found Arntl to be a master regulator in rejuvenation, corroborating its earlier identification as the TF with the most significant age-related decline in activity in at least one prior analysis. However, only three other matching TFs were identified, with the sign of TF activity changes varying substantially by cell type. This suggests notable differences between transcriptional changes associated with aging and the regulators of rejuvenation. It also uncovered previously undocumented mediators of rejuvenation interventions. Moreover, in cases where the transcriptional mediators are known, our analysis provides novel insights.

For example, while the AP-1 complex formed by Fos and Jun has been described to regulate diverse cell functions, and in particular the inflammaging response, our analysis further demonstrates that different subunits and cofactors serve as master regulators of the response to specific interventions. In light of our findings and a recent study that highlighted an up-regulation of the Jun-Fos dimer expression, which is accompanied by increasing inflammation, it is plausible that AP-1 dimers composed of other subunits are responsible for inducing anti-aging effects.

Apart from the AP-1 complex, our analysis revealed the transcriptional stress response TFs NFE2L2 and MAF as master regulators of certain rejuvenation interventions in different cell types. Indeed, MAF and NFE2L2 have been shown to dimerize and regulate gene expression programs that protect against oxidative stress, which are lost with age. Moreover, over-expressing MAF has been shown to rescue these protective expression programs and preserve fitness in an animal aging model. Conversely, the reduced activity of NFE2L2 leads to increased cellular senescence and inflammation.

Link: https://doi.org/10.18632/aging.206105

Hearing loss emerges from the loss of sensory hair cells in the inner ear, or from the loss of axonal connections between these cells and the brain. It remains somewhat unclear as to which of these losses is the more important; the evidence is mixed. Age-related hearing loss is age-related because the accumulated damage of aging creates a hostile environment for hair cells and their axons. The precise mechanisms of dysfunction are debated, which are more or less important. The development of therapies is at the present time focused on replacement of hair cells rather than on addressing the root causes of hair cell and axon loss.

Age-related hearing loss (ARHL), recognized as the third most common chronic geriatric disease, affects approximately half of adults aged 85 years and over, significantly impairing the health and well-being of the elderly population, leading to communication challenges, social isolation, and cognitive decline. The relationship between aging and ARHL is complex, as the same molecular and cellular mechanisms that drive the aging process also contribute to the deterioration of auditory function. As the body ages, the auditory system becomes increasingly susceptible to the cumulative effects of multiple degenerative processes associated with aging, leading to the progressive hearing loss characteristic of ARHL. Despite advancements in identifying the age-related cellular and molecular changes in the inner ear, the long-standing question that remains is which precise mechanisms underlie the age-dependent degeneration of cochlear structure and function, as well as which methods can be used to preserve or reverse these processes.

Dysregulation of cellular pathways like senescence, autophagy, and oxidative stress, in addition to molecular pathways regulated by AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor-1 (IGF-1), and sirtuins (SIRTs) have each been implicated in hearing loss progression, but the specific causative factors and their direct roles on molecular and cellular pathways that lead to cochlear degeneration are not fully elucidated. Understanding how these pathways affect postmitotic hair cells, the stria vascularis, and the spiral ganglion cells is vital for elucidating the mechanisms of ARHL and developing therapeutic interventions to prevent or mitigate ARHL.

Calorie restriction (CR), well recognized for its healthspan and lifespan-extending properties, has also been shown to slow ARHL in both rodents and primates, but the specific molecular pathways modified by CR in the inner ear and the most effective CR mimetic compounds remain unclear. However, molecules targeting oxidative stress and mitochondrial dysfunction or using CR mimetics such as metformin and nicotinamide mononucleotide (NMN), as well as the potential of senolytics or senomorphics, may offer new treatment strategies for ARHL. Characterizing these fundamental aging pathways will not only enhance our understanding of general aging processes but also illuminate their role in ARHL.

Link: https://doi.org/10.3390/ijms25179705

The immune system declines with age, becoming overactive and inflammatory (inflammaging) while at the same time losing its capacity to destroy pathogens and errant cells (immunosenescence), and also becoming dysregulated and harmful in its participate in processes of tissue maintenance. It is well established that the practice of either intermittent fasting or calorie restriction can slow the progression of aging and, specifically, improve the function of the aging immune system. Since these interventions appear to produce their beneficial effects on cell behavior largely through improved autophagy, autophagy should most likely be the starting point for any consideration of how immune function is improved.

Autophagy is a complex set of processes that maintain the health of a cell by recycling excess and damaged proteins and structures, delivering them to a lysosome where they are dismantled into raw materials for further protein synthesis. Many of the approaches shown to modestly slow aging in laboratory species involve improvements in autophagy, as they are all different ways to tinker with the extensive regulatory machinery that controls the cellular response to low nutrient availability.

Up to a point, greater autophagy protects against damage and cell stress, and this adds up over time. Improved autophagy can reduce the pace at which cells become senescent, and thus lower the overall burden of lingering senescent cells in aged tissues. This reduces pro-inflammatory signaling. Similarly, improved autophagy can dampen innate immune reactions to the molecular damage of aging.

Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging

Aging is a complex process, associated with the accumulation of damaged molecules, progressive loss in structure and function of cells, tissues, and organs, and increased vulnerability to death. Even if the aging process is multifaceted and diverse, laboratory manipulation of genes in different laboratory model animals has increased the lifespan of these organisms. Most genes that are associated with increasing lifespan are part of the nutrient-sensing pathway and the mutation in these genes mimics the state of food shortage. Different mechanisms of fasting and calorie restriction (CR) have been linked with healthy aging trajectories in different organisms. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored.

Alongside other systems in the body, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. Of the two systems, the adaptive part of the immune system is most impacted by aging. Inflammation is a crucial process that facilitates the maintenance and restoration of tissue and the clearance of pathogens. On the other hand, chronic inflammatory processes are linked with different pathologies, like rheumatoid arthritis. Aside from this pathological involvement of chronic inflammation, the aging process is linked with a low-grade, chronic, and sterile inflammation (an inflammation without infection) termed as "inflammaging."

In general, evidence-based scientific experiments on fasting and calorie restriction have shown to promote healthy aging as well as to alleviate some markers of immunosenescence and inflammaging. Thus, similar to regular exercise, a vegetarian diet, etc., fasting/calorie restriction should also be considered part of a healthy lifestyle. Furthermore, fasting and calorie restriction increases the fitness of the immune system in fighting infection and cancer which are more common in the elderly. However, more data are needed especially on nutritional approaches including, the amount of nutrients, type of nutrients, and combination of nutrients that promote healthy aging and an effective immune response in humans. Furthermore, strategies on how to integrate fasting/calorie restriction in boosting immune response like the length of the intervention, and at what age is best to start fasting still need to be standardized so that its actual effect on the aging immune system can be clarified and used.