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- Blood Brain Barrier Disruption Correlates with Worse Memory Function in Older People
- Experts on Aging Disagree About Aging
- The Thalamus Degenerates Following Stroke, Producing Neural Dysfunction
- Reviewing Fecal Microbiota Transplantation as an Approach to Treat Aging
- Is Most of the Detected Cellular Senescence in Tissue Actually Senescent Immune Cells?
- Olympic Champions Exhibit Slowed Epigenetic Aging versus Other Athletes
- A Transcriptomic Map of Age-Related Loss of Muscle Regenerative Capacity
- The Pro-Aging Metabolic Reprogramming Hypothesis
- Skeletal Muscle Loss Correlates with Dementia Risk
- Towards Faster Bioprinting of Replacement Tissue
- Pulsed MYC Overexpression Triggers Muscle Growth in Mice
- Suggesting that Upregulation of Anti-Inflammatory Signaling is the Best Approach to Age-Related Chronic Inflammation
- Stimulation of the Hypothalamus to Restore Function Following Spinal Cord Injury
- Greater Mitochondrial Fragmentation Correlates with Loss of Muscle Function
- Cellular Senescence and Inflammation in Osteoarthritis
Blood Brain Barrier Disruption Correlates with Worse Memory Function in Older People
https://www.fightaging.org/archives/2024/12/blood-brain-barrier-disruption-correlates-with-worse-memory-function-in-older-people/
Healthy, cognitively normal older people are called healthy and cognitively normal because their degeneration is not yet severe enough to be called disease. Whether or not one has an age-related disease isn't as binary as the regulators would like it to be, however. Loss of function is a progression, growing over time, and disease status is just a line in the sand drawn somewhere along that path. The average healthy older person is impaired to some measurable degree in comparison to their younger self, and that impairment derives from the accumulation of damage and dysfunction in cells and tissues throughout the body.
As an illustration of this point, today's open access paper provides data on cognitively normal older people. The researchers show that measurable dysfunction in the blood-brain barrier correlates with loss of memory function. When the blood-brain barrier leaks, it allows unwanted molecules and cells into the brain, where they can provoke chronic inflammation. This is harmful to brain function. This damage and cognitive decline definitively exist, and yet these people are considered healthy and cognitively normal in the present system of medicine. One might hope that this way of looking at things will change dramatically as the first rejuvenation therapies emerge into widespread use.
Cross-sectional and longitudinal relationships among blood-brain barrier disruption, Alzheimer's disease biomarkers, and cognition in cognitively normal older adults
The deposition of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles has been the focus of Alzheimer's disease (AD) research. Both Aβ and tau show relationships with cognition that are particularly malignant when the two proteins occur together. Recent research suggests that neurovascular factors including blood-brain barrier disruption (BBBd) may be an early biomarker of human cognitive dysfunction and possibly an underlying mechanism of age-related cognitive decline or AD. BBBd is implicated in both aging and AD, with BBBd observed in regions susceptible to neurodegeneration and important for cognitive function. Studies have also identified that BBBd is associated with cognitive deficits, independent of AD pathology and atrophy. However, there is also evidence that pathological protein aggregation may be related to BBBd. These findings highlight the need to further consider relationships between BBBd and pathological protein aggregation, and to examine in greater depth the likely complex processes that drive age related cognitive decline and perhaps AD.
The current model of AD is a sequential cascade: first Aβ deposition, then tau pathology, neurodegeneration, and eventually dementia. Some research points to BBBd as a potential early biomarker and underlying mechanism of cognitive decline. The BBB is essential for brain homeostasis, and its disruption has been implicated in AD pathogenesis. BBBd may facilitate the entry of neurotoxic substances into the brain and impair Aβ clearance, contributing to plaque accumulation. This raises critical questions about how BBBd fits into the current AD model and whether it acts as an early or parallel process that exacerbates neurodegeneration and cognitive decline.
We used dynamic contrast-enhanced MRI (DCE-MRI) and positron emission tomography (PET) imaging in cognitively normal older adults to explore how BBBd correlates with brain atrophy and cognitive function, and whether these relationships are influenced by Aβ or tau. We found that greater BBBd in the hippocampus (HC) and an averaged BBBd-susceptible region of interest (ROI) were linked to worse episodic memory, with interactions between BBBd and atrophy influencing this relationship, independent of Aβ and tau. However, there were no significant relationships between BBBd and non-memory cognitive performance. In participants with longitudinal AD biomarker and cognitive data acquired prior to DCE-MRI, faster longitudinal entorhinal cortex (EC) tau accumulation and episodic memory decline were associated with greater HC BBBd, independent of global Aβ changes and regional atrophy.
Taken together, both our cross-sectional and longitudinal findings suggest that BBBd may play a role in the early stages of cognitive decline, independent of the key biomarker of AD, Aβ. The significant relationships among HC BBBd, atrophy, and memory performance point to the potential of BBBd as an early indicator of cognitive decline.
Experts on Aging Disagree About Aging
https://www.fightaging.org/archives/2024/12/experts-on-aging-disagree-about-aging/
The lack of consensus on aging is well known within the field of aging research and the longevity industry - good luck in trying to get any two research groups to agree on any specific declaration regarding the causes and progression of aging! That there are few points of consensus on aging is perhaps less well appreciated outside the field. Yet this seems inevitable for any very complex area of study. Researchers have produced an immense and growing body of data, but connecting these pieces together into a coherent map of cause and consequence remains a work in process, and will likely continue for decades yet.
We live in an era in which one can measure gene expression throughout the body and show how it changes with age, but we struggle to turn this data into an understanding of cause and effect. It seems likely that the fastest path forward to building that map of cause and consequence in aging is the direct one: produce therapies that repair and reverse specific age-related changes, and observe the results. Therapies targeting causes will do well. Therapies targeting consequences, not so well.
Disagreement on foundational principles of biological aging
While the field of aging has seen major advances, e.g. extending the lifespan of all major model organisms through genetic, pharmacological, and dietary interventions, there is no convincing evidence of the exact causes and mechanisms of aging, and no effective treatment proved to slow down or reverse the aging process in humans. Even the definitions of aging in the published literature are widely different and not easily reconcilable. Understanding how scientists who study aging view this process could help bridge this gap and accelerate progress in the field. With this in mind, we conducted a survey on the most basic features of aging with the participants of the 2022 Systems Aging Gordon Research Conference.
Notwithstanding the broad disagreement revealed by this survey, the answers nevertheless show elements of shared thinking, with most respondents aligning on certain principles and features of aging, as well as on what aging is not. First, there is a general consensus that aging - however it is defined - exists, has identifiable causes and effects, and can be studied experimentally. These views may be compared with the idea that aging as a unified phenomenon does not exist. Second, most scientists agree that aging is inherently deleterious, involving the accumulation of harmful changes, damage, degeneration, and loss of function. Third, aging is widely regarded as a process, with most respondents explicitly referring to it as such. It has certain characteristics, manifestations, a rate of progression, and outcomes - most notably, leading to death. Fourth, aging may be targeted, modulated, regulated, accelerated, and decelerated. Fifth, the aging process has a definable starting time or period within an organism's life. Sixth, rejuvenation is acknowledged as a real phenomenon (in that it can be defined), implying that aging can theoretically be reversed, not just slowed - though this does not imply feasibility. Seventh, a clear distinction exists between chronological age and biological age.
It is clear from the responses that aging remains an unsolved problem in biology. Scientists disagree over whether it is a universal property of life, whether it is pathological or normal, whether it is subject to natural selection, and whether it has a particular purpose. Interestingly, almost all respondents answered all questions, suggesting that they have a clear opinion on the subject. Yet, their responses were widely different. So, while most scientists think they understand the nature of aging, apparently their understanding differs. It is also clear from the responses that scientists working in the aging field have mixed opinions on the most fundamental definitions and mechanisms in the biology of aging. In the whole survey, no question received more than 50% of common responses. When discussing the biology of aging with colleagues, we often assume we are talking about the same process, but clearly, we are not. Some of us consider aging to be a loss of function, some accumulation of damage, some an increase in mortality rate, etc. While these and other features often go hand in hand, they are fundamentally different and therefore may be targeted differently.
Despite the importance of foundational issues in the biology of aging and the clear lack of consensus on these issues, little effort is being placed into directly addressing them. Moreover, there is a clear disconnect between what respondents think are the most important unanswered questions in the field and the ongoing research in the field. It is not necessarily because scientists are biased toward what they do. It is more likely that this is because these are very difficult questions to answer or to even design proper experiments and statistical treatments to address them. A part of the problem is also that most terms in the field are ill-defined, causing confusion due to different emphasis in different contexts and due to the variable use of the terms, including the term aging. For example, aging can be described as normal, normative, successful, healthy, pathological, premature, accelerated, etc., but what exactly all these terms mean is rarely discussed.
More generally, it is clear from the survey that in the most commonly referenced sequence of events - damage causes functional decline causes age-related disease causes mortality - different events are viewed as aging by different respondents. This may present a critical impediment to developing the most effective strategies to target aging. Depending on what one considers the essence of aging, experimental strategies may be disconnected from aging and directed either to the causes of aging and other upstream events or to the consequences and associations of aging.
The Thalamus Degenerates Following Stroke, Producing Neural Dysfunction
https://www.fightaging.org/archives/2024/12/the-thalamus-degenerates-following-stroke-producing-neural-dysfunction/
A stroke is caused by rupture or blockage of a blood vessel in the brain. Rupture of blood vessels in the brain can occur due to the combination of (a) mechanisms that weaken blood vessel walls and (b) raised blood pressure, both of which are commonplace in older individuals. Blockage arises due to the breakup of an unstable atherosclerotic plaque, sending debris downstream. This is by far the most common cause of stroke, and one of the leading forms of human mortality. Since plaque rupture can also causes heart attack and fatal embolism elsewhere in the body, we should perhaps all pay more attention to atherosclerosis and the development of means to reverse its progression.
In an environment in which atherosclerosis cannot be reversed reliably or to any great degree, as is presently the case, a great deal of attention goes instead to coping with the aftermath of blocked blood vessels. Researchers try to find ways to repair some of the damage done to survivors, or as in today's open access paper, better understand how it is that a stroke occurring in a small part of the brain can produce lasting dysfunction throughout the brain. The answer appears to be that stroke provokes degeneration of the thalamus, a part of the brain thought to act as a form of relay, central to the flow of information between many different areas of the brain. Why this degeneration occurs following a stroke is an open question: one might suspect the usual culprit of excessive inflammatory signaling, disruptive to function in so very many ways.
Study uncovers promising new target for stroke treatment
Strokes leave behind an area where brain cells have died, called a lesion. However, this cannot explain the widespread consequences of stroke, limiting scientists' and clinicians' ability to treat them. A new study reveals that degeneration of the thalamus - an area of the brain distinct from the stroke lesion - is a significant contributor to post-stroke symptoms. "This is both good and bad news. The bad news is the impact to the brain caused by stroke is not limited to the lesion seen on a brain scan. The good news is the area that shows abnormal electrical activity outside the lesion might be treatable with innovative new therapies."
Damage to brain tissue near the stroke lesion was not the primary cause of abnormal brain electrical activity. Instead, these abnormalities were related to the thalamus, a structure located deep in the brain's centre that acts like a hub connecting numerous brain areas and activities. More than the lesion alone, the amount of degeneration in the thalamus predicted the amount of abnormal brain electrical activity measured using magnetoencephalography (MEG), and the individual's language and cognitive deficits.
Secondary thalamic dysfunction underlies abnormal large-scale neural dynamics in chronic stroke
Stroke causes pronounced and widespread slowing of neural activity. Despite decades of work exploring these abnormal neural dynamics and their associated functional impairments, their causes remain largely unclear. To close this gap in understanding, we applied a neurophysiological corticothalamic circuit model to simulate magnetoencephalography (MEG) power spectra recorded from chronic stroke patients. Comparing model-estimated physiological parameters to those of controls, patients demonstrated significantly lower intrathalamic inhibition in the lesioned hemisphere, despite the absence of direct damage to the thalamus itself. We hypothesized that this disinhibition could instead be related to secondary degeneration of the thalamus, for which growing evidence exists in the literature.
Further analyses confirmed that spectral slowing correlated significantly with overall secondary degeneration of the ipsilesional thalamus, encompassing decreased thalamic volume, altered tissue microstructure, and decreased blood flow. Crucially, this relationship was mediated by model-estimated thalamic disinhibition, suggesting a causal link between secondary thalamic degeneration and abnormal brain dynamics via thalamic disinhibition. Finally, thalamic degeneration was correlated significantly with poorer cognitive and language outcomes, but not lesion volume, reinforcing that thalamus damage may account for additional individual variability in poststroke disability. Overall, our findings indicate that the frequently observed poststroke slowing reflects a disruption of corticothalamic circuit dynamics due to secondary thalamic dysfunction, and highlights the thalamus as an important target for understanding and potentially treating poststroke brain dysfunction.
Reviewing Fecal Microbiota Transplantation as an Approach to Treat Aging
https://www.fightaging.org/archives/2024/12/reviewing-fecal-microbiota-transplantation-as-an-approach-to-treat-aging/
The composition of the gut microbiome is influential on health, perhaps to a similar degree as diet and exercise. Unfortunately this composition, the relative numbers of different microbial species, changes with age in ways that promote chronic inflammation and reduce the generation of beneficial metabolites necessary to tissue function. Researchers have shown that it is possible to rejuvenate an aged gut microbiome, producing a lasting reset to a more youthful configuration with a single intervention. Approaches include flagellin immunization to guide the immune system into destroying harmful microbiomes, and fecal microbiota transplantation from a young donor. While in principle one could achieve similar outcomes using tailored high dose probiotics, at this time available forms of probiotic therapy produce only short-term alterations to the gut microbiome.
In today's open access paper, researchers discuss fecal microbiota transplantation as an approach to treat aging as a medical condition. Adjusting the aged gut microbiome to a youthful configuration is a form of rejuvenation therapy, repairing a type of damage in order to remove the downstream consequences of this damage. Fecal microbiota transplantation from young donors to old recipients works well in animal studies, improving health and extending life. There is some use in human medicine, but the inability to completely control outcomes resulting from fecal microbiota transplantation suggests that the field will probably ultimately favor efforts to develop forms of analogous high dose probiotic therapy.
Fecal microbiota transplantation, a tool to transfer healthy longevity
The gut microbiome has emerged as an important contributor influencing host aging. The gut microbiome comprises an extensive population of microorganisms, predominantly different phyla of bacteria and, to a lesser degree, also viruses, protozoa, and fungi. Among other physiological roles, the gut microbiome supports the digestion and absorption of food, generates vitamins and nutrients, exerts a positive effect on lipid metabolism, maintains intestinal integrity, and metabolizes fibers into bioactive short-chain fatty acids (SCFAs), which have immunomodulatory, anti-inflammatory, and anti-cancer capabilities.
Microbe-derived SCFAs also play an important role in gut-brain intercommunication, with gut microbiota imbalances promoting brain alterations and neurodegeneration. Since these microorganisms play significant roles in immunological, metabolic, and physiological functions of host health, increasing evidence demonstrate that shifts in host-microbiome balance have a clinical impact in the pathogenesis of several metabolic disorders, age-related diseases, and other major conditions. In this scenario, personalized gut microbiome remodeling is evolving as a promising new era of therapeutic interventions against age-associated chronic diseases.
Interestingly, exceptional longevity of centenarians and semi-supercentenarians, who are less susceptible to inflammation, infectious diseases, and many other aging-associated dysfunctions, is also associated to the maintenance of a higher gut microbiome diversity of core microbiota species and a higher prevalence of health-associated gut-microorganisms compared to younger individuals. For example, Akkermansia muciniphila is present at higher abundance in centenarians. Conversely, progeria patients and progeroid mouse models exhibit a significant loss of this particular strain.
Gut microbiome from centenarians also presents high capacity for central metabolism, including glycolysis, amino acid metabolism and fermentation to SCFAs. Likewise, microbiome-related gene pathways related to bile acid metabolism - including secondary bile acid with antimicrobial activity - are suggestive of reduced levels of infections among centenarians. Furthermore, administration of A. muciniphila by oral gavage is sufficient to enhance healthspan and to promote lifespan in progeroid mice models, partially by the restoration of correct secondary bile acid metabolism and other metabolites (arabinose, ribose, inosine) in the intestinal tract of these animals.
Restoring a healthy gut microbiome via Fecal Microbiota Transplantation (FMT) is receiving extensive consideration to therapeutically transfer healthy longevity. Herein, we comprehensively review the benefits of gut microbial rejuvenation - via FMT - to promote healthy aging, with few studies documenting life length properties. Throughout this review, we examine the impact of gut microbiome on host aging, and we address the potential therapeutic advantages of modulating gut microbiome via FMT. Preclinical and clinical research, along with current gaps, including safety and risks associated to FMT, are thoroughly examined. By addressing these objectives, this manuscript enhances our understanding of FMT-based interventions aimed at promoting healthier longevity.
Is Most of the Detected Cellular Senescence in Tissue Actually Senescent Immune Cells?
https://www.fightaging.org/archives/2024/12/is-most-of-the-detected-cellular-senescence-in-tissue-actually-senescent-immune-cells/
Cells become senescent on reaching the Hayflick limit to replication, or in response to stress and damage. A senescent cell ceases replication and generates pro-inflammatory signals. In the short term this is usually helpful, attracting the immune system to assist in issues such as regeneration following injury or cells with potentially cancerous DNA damage. When sustained for the long term, however, the signaling of senescent cells is harmful. Following the realization that senescent cells accumulate with age and that their inflammatory signaling contributes to degenerative aging, assessments of the burden of senescence used a few consensus markers, such as β-galactosidase and p16 expression.
As time went on, it became clear that senescence is more varied a state than first appreciated, differing by cell type, cause of senescent, time spent senescent, and no doubt other factors. While the initial consensus markers for senescence continue to be used, it is now generally accepted that these markers might not be capturing the picture originally thought to be the case. Today's open access paper is an example of the sort of research into the burden of senescence and its relationship to aging presently taking place in this new context. Researchers provide evidence for p16 expression in tissues to be a marker of resident or infiltrating immune cell senescence, not tissue cell senescence. Their interpretation is that this puts more of an emphasis on the aging of the immune system as a driver of systemic aging throughout the body.
Distribution and impact of p16INK4A+ senescent cells in elderly tissues: a focus on senescent immune cell and epithelial dysfunction
Cellular senescence, as a major player among hallmarks of aging, has been reported as being able to accumulate senescent cells in various tissues during aging process. Cellular senescence can cause a halt in the proliferation of functional cells, ultimately resulting in organic dysfunction and induce sterile chronic inflammation through the secretion of senescence-associated secretory phenotypes (SASPs), which are known as 'inflammaging'. Previous studies applying senolytics or selective cytotoxicity in p16INK4A-overexpressed cells in aged mice have been supported the notion that removal of senescent cells can be alleviate not all but many aging-related phenotypes and lead to the prolongation of life span. Although the final phenotypes resulting from the removal of senescent cells have been confirmed in multiple previous studies, information about the specific cell types that accumulate as senescent cells and their removal remains scarce.
Organs are composed of two major components: the parenchyma and the stroma. Parenchymal cells, responsible for executing organ-specific functions, often exhibit rapid proliferation and turnover rates. Examples include gastrointestinal tract epithelial cells and skin keratinocytes. Conversely, the tissue stroma can be further categorized into cells providing structural support and immune cells. Cells providing structural support (hereinafter referred as structural stromal cells), such as fibroblasts and smooth muscle cells produce extracellular matrix (ECM) components and maintain tissue structures. The remaining stromal cells are immune cells, which may be resident, such as liver Kupffer cells and skin Langerhans cells, or infiltrating, such as bone marrow-derived cells and lymphocytes. These cells are involved in protecting organs from foreign invaders, chronic inflammation, and tissue regeneration related to the aging process.
Our research indicates that fully senescent p16INK4A+ cells are rarely identified in the parenchyma of organic tissues and in the stromal cells crucial for structural maintenance, such as fibroblasts and smooth muscle cells. Instead, p16INK4A+ cells are more commonly found in immune cells, whether they reside in the organ or are infiltrating. Notably, p16INK4A+ senescent T cells have been observed to induce apoptosis and inflammation in colonic epithelial cells through Granzyme A / protease-activated receptor signaling, compromising the integrity of the epithelial lining. This study showed that the senescence of immune cells could affect the phenotypical change of the parenchymal cells in the elderly and suggests that targeting immunosenescence might be a strategy to control functional decline in this population.
Olympic Champions Exhibit Slowed Epigenetic Aging versus Other Athletes
https://www.fightaging.org/archives/2024/12/olympic-champions-exhibit-slowed-epigenetic-aging-versus-other-athletes/
Epidemiological data consistently shows that professional athletes live longer than the rest of the population. Here, researchers compare top tier professional athletes with other athletes, and find that those who succeed in competition appear to show slowed epigenetic aging. If we believe that epigenetic clocks are a decent measure of biological age, and that winning is a decent proxy for degree of physical fitness, then this seems a reasonable outcome, given what is known of the dose-response curve for exercise effects on mortality.
The lifestyle patterns of top athletes are highly disciplined, featuring strict exercise regimens, nutrition plans, and mental preparation, often beginning at a young age. Recently, it was shown that physically active individuals exhibit slowed epigenetic aging and better age-related outcomes. Here, we investigate whether the extreme intensity of physical activity of Olympic champions still has a beneficial effect on epigenetic aging. To test this hypothesis, we examined the epigenetic aging of 59 Hungarian Olympic champions and of the 332 control subjects, 205 were master rowers.
We observed that Olympic champions exhibit slower epigenetic aging, applying seven state-of-the-art epigenetic aging clocks. Additionally, male champions who won any medal within the last 10 years showed slower epigenetic aging compared to other male champions, while female champions exhibited the opposite trend. We also found that wrestlers had higher age acceleration compared to gymnasts, fencers, and water polo players. We identified the top 20 genes that showed the most remarkable difference in promoter methylation between Olympic champions and non-champions. The hypo-methylated genes are involved in synaptic health, glycosylation, metal ion membrane transfer, and force generation. Most of the hyper-methylated genes were associated with cancer promotion. The data suggest that rigorous and long-term exercise from adolescence to adulthood has beneficial effects on epigenetic aging.
A Transcriptomic Map of Age-Related Loss of Muscle Regenerative Capacity
https://www.fightaging.org/archives/2024/12/a-transcriptomic-map-of-age-related-loss-of-muscle-regenerative-capacity/
Researchers here produce a map of transcription in muscle regeneration in mice of various ages, separated by cell type and time following muscle injury. The results are interesting, and show that the participation of the immune system in regeneration becomes dysregulated in older animals. Muscle stem cell function also declines, as might be expected. Restoring the aged immune system and aged stem cell populations are both sizable challenges facing those intent on developing the first rejuvenation therapies, but clearly very important.
The immune, stromal, and myogenic cells found in skeletal muscle contribute to muscle maintenance and regeneration by regulating muscle stem cell (MuSC) quiescence, proliferation, and differentiation. It has been shown that an imbalance in immune cell populations during injury response can disrupt proper muscle repair. To investigate this, we compared the change in cell-type abundances over our regeneration time course between young, old, and geriatric muscles. As expected, neutrophils are one of the first immune cell types to peak in abundance. We also observe monocyte and macrophage populations that express pro-inflammatory markers like Ccr2 and patrolling markers like Ctsa responding soon after injury (days 1-2) when we expect the muscle environment to be enriched with pro-inflammatory cytokines. Monocytes and macrophages that express pro-inflammatory markers clear cellular debris and promote myogenic cell proliferation. There should be a shift to monocytes and macrophages that express anti-inflammatory marker C1qa at days 4-7 following injury.
We do broadly observe a shift from monocytes and macrophages that express pro-inflammatory markers to anti-inflammatory markers, but there are significant differences by age. This difference in monocyte and macrophage dynamics could explain the age-related decline in muscle repair because if macrophages do not clear cellular debris or promote myogenic cell proliferation and differentiation, the muscle remains inflamed and there are repeated cycles of necrosis and regeneration. The damaged myofibers are then replaced with adipose tissue, fibrotic tissue or bone, instead of new myofibers. In addition to age-specific differences in the dynamics of the monocyte and macrophage populations, we observe age-specific differences in the T cell dynamics. There is miscoordination of the T cell response, which in turn could impact the ability of aged muscle to repair itself.
One factor that has been shown to contribute to the reduced functionality of MuSCs in aged tissues is the establishment of senescent MuSCs. Our data is supportive of a senescent-like MuSC and progenitor population that is more abundant in the geriatric mice, suggesting stalled stem cell self-renewal in mouse muscle aging. Together, these observations point to a transitory senescent-like cell population that is abundant at the self-renewing MuSC stage during regeneration across all ages of mice. This population of senescent-like MuSCs increases within the injury zone and in older mice, suggesting that a stalled stem cell self-renewal state underlies the regenerative dysfunction in mouse aging.
The Pro-Aging Metabolic Reprogramming Hypothesis
https://www.fightaging.org/archives/2024/12/the-pro-aging-metabolic-reprogramming-hypothesis/
There are a great many theories of aging. This is in part because it is easier to theorize than to develop concrete proof linking root causes to downstream effects in the biochemistry of aging. Cells are enormously complex systems, and tissues made up of cells are even more complex. Vast mountains of data relating to aging have been produced, layer upon layer of data, from changes in transcription to changes in cell behavior to changes in organ function to visible manifestations of age-related disease. Everything in the body interacts with everything else. Determining what is cause and what is effect is very challenging. So there is plenty of room for hypothesis, and most of those hypotheses will turn out to be wrong in some way.
Despite recent progress in understanding the biology of aging, the field remains largely fragmented due to the lack of a central organizing hypothesis that could provide a framework for investigating how fundamental upstream biological processes can regulate the timing of age onset and progression. While numerous theories on aging have been proposed and efforts have been made to create unifying theories that incorporate various aging-related phenotypes and mechanisms, none of them constitutes a fully comprehensive doctrine for understanding the aging process in its entirety. There are ongoing debates on whether the aging process is programmed or stochastic. The programmed theory views aging as a continuation of the orderly genetic program that guides early growth and development, while the stochastic hypothesis considers aging to be a result of the accumulation of random errors. However, neither theory can independently explain the complexity of aging.
The Pro-aging metabolic reprogramming (PAMRP) theory proposed here posits that aging is determined by degenerative changes in cellular metabolism that occur over time. Specifically, aging has both a programmed and stochastic nature, with its onset requiring both the preexistence of pro-aging substrate (PAS) buildup through degenerative metabolic alterations and the emergence of pro-aging triggers (PAT) induced by stochastic events. The convergence of PAS and PAT initiates metabolic reprogramming (MRP), predisposing the body to cellular reprogramming (CRP) and genetic reprogramming (GRP) and ultimately leading to a self-perpetuating progression of the aging process governed by the genetic program.
The human body's metabolism is genetically preprogrammed but can be epigenetically reprogrammed for good or bad outcomes depending on the specific context. As organisms age, there are significant alterations in metabolic pathways within cells, including shifts in energy production, nutrient utilization, and waste-management processes. Initially, this MRP serves as an adaptive mechanism to cope with varying stress conditions. However, these adaptations come at the cost of accumulating molecular damage, including oxidative stress-induced DNA mutations, protein aggregation, and mitochondrial dysfunction, which are hallmarks of and substrates for aging. Over time, this MRP becomes maladaptive, contributing to a self-perpetuating cycle that maintains the altered metabolic state and exacerbates degenerative changes in gene expression and regulatory mechanisms. Ultimately, once a threshold level is reached, MRP triggers the genetic aging program, impacting cellular function, tissue homeostasis, and overall organismal health.
Skeletal Muscle Loss Correlates with Dementia Risk
https://www.fightaging.org/archives/2024/12/skeletal-muscle-loss-correlates-with-dementia-risk/
The incidence and progression of many specific diseases and declines of aging correlate with one another. Insofar as aging as a whole emerges from a shared set of underlying forms of cell and tissue damage, one would expect this to be the case. Still, some consequences of aging feed into other consequences, making them worse. The challenge lies in teasing out the differences between these two classes of mechanism from human epidemiological data. The research noted here looks at muscle loss and dementia. Aging leads to chronic inflammation and mitochondrial dysfunction, both of which independently negatively impact the ability to maintain muscle mass and the function of the brain. Equally, loss of muscle mass implies loss of myokine signaling and lower levels of activity, both of which could speed neurodegeneration. Which is more important? That is a hard question to answer given only human study data to work with.
As people grow older, they begin to lose skeletal muscle mass. Because age-related skeletal muscle loss is often seen in older adults with Alzheimer's disease (AD) dementia, this study aimed to examine whether temporalis muscle loss (a measure of skeletal muscle loss) is associated with an increased risk of AD dementia in older adults. The temporalis muscle is located in the head and is used for moving the lower jaw. Studies have shown that temporalis muscle thickness and area can be an indicator of muscle loss throughout the body.
Researchers used baseline brain MRI exams from the Alzheimer's Disease Neuroimaging Initiative cohort to quantify skeletal muscle loss in 621 participants without dementia (mean age 77 years). The researchers manually segmented the bilateral temporalis muscle on MRI images and calculated the sum cross-sectional area (CSA) of these muscles. Participants were categorized into two distinct groups: large CSA (131 participants) and small CSA (488 participants). Outcomes included subsequent AD dementia incidence, change in cognitive and functional scores, and brain volume changes between the groups. Median follow-up was 5.8 years.
Based on their analysis, a smaller temporalis CSA was associated with a higher incidence risk of AD dementia. Furthermore, a smaller temporalis CSA was associated with a greater decrease in memory composite score, functional activity questionnaire score and structural brain volumes over the follow-up period. "We found that older adults with smaller skeletal muscles are about 60% more likely to develop dementia when adjusted for other known risk factors."
Towards Faster Bioprinting of Replacement Tissue
https://www.fightaging.org/archives/2024/12/towards-faster-bioprinting-of-replacement-tissue/
3-D tissue printing has been a work in progress for going on twenty years at this point. The biggest challenges are (a) that it remains slow and expensive, and (b) producing sufficient microvasculature to support the printed tissue. Inroads are being made on both of these issues, such as the work noted here, but progress is incremental. It remains to be seen as to when the much anticipated 3-D printed organs made from a patient's own cells and ready for transplantation will emerge - at this point, the creation of functional tissues much larger than a few millimeters is not a practical proposition for most use cases.
Bioprinting allows researchers to build 3D structures from living cells and other biomaterials. Living cells are encapsulated in a substrate like a hydrogel to make a bioink, which is then printed in layers using a specialized printer. These cells grow and proliferate, eventually maturing into 3D tissue over the course of several weeks. However, it's difficult to achieve the same cell density as what's found in the human body with this standard approach. That cell density is essential for developing tissue that's both functional and can be used in a clinical setting. Spheroids, on the other hand, offer a promising alternative for tissue bioprinting because they have a cell density similar to human tissue.
While 3D printing spheroids offers a viable solution to producing the necessary density, researchers have been limited by the lack of scalable techniques. Existing bioprinting methods often damage the delicate cellular structures during the printing process, killing some of the cells. Other technologies are cumbersome and don't offer precise control of the movement and placement of the spheroids needed to create replicas of human tissue. Or the processes are slow.
To address these issues, researchers developed a new technique called High-throughput Integrated Tissue Fabrication System for Bioprinting (HITS-Bio). HITS-Bio uses a digitally controlled nozzle array, an arrangement of multiple nozzles that moves in three dimensions and allows researchers to manipulate several spheroids at the same time. The team organized the nozzles in a four-by-four array, which can pick up 16 spheroids simultaneously and place them on a bioink substrate quickly and precisely. The nozzle array can also pick up spheroids in customized patterns, which can then be repeated to create the architecture found in complex tissue. To test the platform, the team set out to fabricate cartilage tissue. They created a one-cubic centimeter structure, containing approximately 600 spheroids made of cells capable of forming cartilage. The process took less than 40 minutes, a highly efficient rate that surpasses the capacity of existing bioprinting technologies.
Pulsed MYC Overexpression Triggers Muscle Growth in Mice
https://www.fightaging.org/archives/2024/12/pulsed-myc-overexpression-triggers-muscle-growth-in-mice/
Loss of muscle mass is a universal issue in aging, leading a degree that leads to physical frailty. Beyond this, muscle is also metabolically active, such as via the production of myokines, and loss of muscle mass is harmful to the rest of the body via these and other signaling mechanisms that remain to be fully explored. Researchers here note the transcription factor MYC as a target for the development of enhancement therapies producing muscle growth. Overexpression of the Yamanaka factor MYC is something to be careful with, given its role in cancer and reprogramming. The classes of therapy presently explored by the reprogramming community, intended to produce repeated short-term expression of Yamanaka factors, seem needed here. Many of the same challenges and caveats will likely apply, such as those regarding targeting to specific cell types and the different cell populations in a tissue requiring different timing and levels of expression for optimal effect.
Several seminal and recent studies suggest that the transcription factor c-Myc (referred to as Myc or MYC for mouse and human genes, respectively) is a key component of skeletal muscle hypertrophic adaptation to loading in animals. Our work using human skeletal muscle biopsies after a bout of resistance exercise (RE), as well as meta-analytical information that combines numerous human muscle gene expression datasets during the recovery period after exercise, indicates that MYC is highly responsive to hypertrophic loading. MYC protein accumulates in human muscle following a bout of RE as well as in response to chronic training. Its expression may also differentiate between low and high hypertrophic responders.
The current investigation details the global gene expression response to a bout of RE after 30 minutes, 3-, 8-, and 24-hours using RNA-sequencing (RNA-seq) in skeletal muscle biopsy samples from healthy untrained humans. Molecular and computational analyses identified MYC as an influential transcription factor controlling the exercise transcriptome throughout the time course of recovery after a bout of RE. Muscle-specific Myc overexpression data from the plantaris and soleus of mice reinforced the human exercise data.
We employed a genetically modified mouse model to induce MYC in a pulsatile fashion specifically in skeletal muscle over 4 weeks to determine if MYC is sufficient for hypertrophy. Our genetically driven pulsatile approach avoids potential negative effects of chronically overexpressing a hypertrophic regulator and more closely mimics the transient molecular response of exercise in skeletal muscle. Pulsed MYC induction resulted in a larger absolute mass (+12.5%) and normalized mass (+20.7%) of the soleus muscle relative to controls. This magnitude of soleus muscle growth is similar to what is observed after 4 weeks of progressive weighted wheel running.
Suggesting that Upregulation of Anti-Inflammatory Signaling is the Best Approach to Age-Related Chronic Inflammation
https://www.fightaging.org/archives/2024/12/suggesting-that-upregulation-of-anti-inflammatory-signaling-is-the-best-approach-to-age-related-chronic-inflammation/
Chronic, unresolved inflammation is a feature of aging. It arises from a varied set of causes, including a growing presence of senescent cells, excess visceral fat tissue in those who are overweight, and mislocalization of mitochondrial DNA that triggers responses evolved to detect bacteria. The end result is disruptive inflammatory signaling that alters cell behavior for the worse, harming tissue structure and function, and accelerating the onset and progression of all of the common age-related conditions. Here, researchers propose that the problem is a more a case of too little anti-inflammatory signaling than too much inflammatory signaling. Can the maladaptive reactions to age-related damage be effectively dampened without also suppressing necessary immune signaling though? Immune suppression remains an unfortunate side-effect of the anti-inflammatory strategies developed to date.
Acute inflammation is elicited by lipid and protein mediators in defense of the host following sterile or pathogen-driven injury. A common refrain is that chronic inflammation is a result of incomplete resolution of acute inflammation and behind the etiology of all chronic diseases, including cancer. However, mediators that participate in inflammation are also essential in homeostasis and developmental biology but without eliciting the clinical symptoms of inflammation. This non-inflammatory physiological activity of the so called 'inflammatory' mediators, apparently under the functional balance with anti-inflammatory mediators, is defined as unalamation. Inflammation in the absence of injury is a result of perturbance in unalamation due to a decrease in the anti-inflammatory mediators rather than an increase in the inflammatory mediators and leads to chronic inflammation.
This concept on the etiology of chronic inflammation suggests that treatment of chronic diseases is better achieved by stimulating the endogenous anti-inflammatory mediators instead of inhibiting the 'inflammatory' mediator biosynthesis with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Furthermore, both 'inflammatory' and anti-inflammatory mediators are present at higher concentrations in the tumor microenvironment compared to normal tissue environments. Since cancer is a proliferative disorder rather than a degenerative disease, it is proposed that heightened unalamation, rather than chronic inflammation, drives tumor growth. This understanding helps explain the inefficacy of NSAIDs as anticancer agents. Finally, inhibition of anti-inflammatory mediator biosynthesis in tumor tissues could act to imbalance unalamation towards a local acute inflammation, triggering an immune response to restore homeostasis and away from tumor growth.
Stimulation of the Hypothalamus to Restore Function Following Spinal Cord Injury
https://www.fightaging.org/archives/2024/12/stimulation-of-the-hypothalamus-to-restore-function-following-spinal-cord-injury/
The brain stores the data of the mind. Restoration of the aged brain will be the most challenging portion of the development of a comprehensive toolkit of rejuvenation therapies, if only because we (largely) cannot resort to outright replacement of component parts, as is the case for the rest of the body. So it is interesting to keep an eye on research into the degree to which the brain can be induced to adapt to damage, to shift and repurpose neural networks to restore lost function. Here, researchers find that stimulating the hypothalamas can enable repurposing of the remaining connections in a damaged but not severed spinal cord.
A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space-time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LHVglut2) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking.
We translated this discovery into a deep brain stimulation therapy of the LH (DBSLH) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBSLH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBSLH was turned off. There were no serious adverse events related to DBSLH. These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI.
Greater Mitochondrial Fragmentation Correlates with Loss of Muscle Function
https://www.fightaging.org/archives/2024/12/greater-mitochondrial-fragmentation-correlates-with-loss-of-muscle-function/
Every cell contains hundreds of mitochondria, descended from ancient symbiotic bacteria. Mitochondrial dynamics are like those of bacteria, in that they constantly divide, fuse together, and swap component parts. Mitochondria are vital to cell function, their primary purpose being to manufacture the chemical energy store molecule adenosine triphosphate (ATP) that powers cell processes. The balance between fission and fusion of mitochondria is known to alter with age, and imbalance generates inflammation and is associated with loss of mitochondrial function. In tissues that require a great deal of energy, such as muscle, mitochondrial dysfunction is likely important in age-related declines.
Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals.
Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2/s/mg) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U.), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density.
Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.
Cellular Senescence and Inflammation in Osteoarthritis
https://www.fightaging.org/archives/2024/12/cellular-senescence-and-inflammation-in-osteoarthritis/
As knowledge grows regarding the age-related accumulation of senescent cells in tissues throughout the body, researchers are establishing a role for senescent cells in many conditions already known to be characterized by the presence of chronic, unresolved inflammatory signaling. When cells become senescent, they cease to replicate and instead devote their energies to secreting inflammatory signals. As the immune system slows down in its clearance of senescent cells with age, their numbers grow and their signaling becomes constant. This is disruptive to tissue structure and function, altering the behavior of surrounding cells in harmful ways and accelerating the onset and progression of age-related conditions.
Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation.
We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.
View the full article at FightAging
