Fight Aging! Newsletter, January 8th 2024
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- Should We Think of Rheumatoid Arthritis as an Age-Related Condition?
- Failing Mitochondrial Quality Control in Aging and Neurodegeneration
- Is Alternative Splicing a Meaningful Cause of Degenerative Aging, or Largely a Downstream Side-Effect?
- Sirtuin 2 Overexpression Fails to Extend Life in Mice
- Standardization to a Single Epigenetic Clock is Much Overdue
- It is Never Too Late to Improve Health by Reducing Calorie Intake
- Air Pollution Implicated as a Contributing Cause of Numerous Age-Related Conditions
- Aptamers to Reduce Inflammatory AGE-RAGE Interaction
- A Look at the Signaling that Produces Bystander Senescence
- Calorie Restriction Mimetics as an Approach to Slow Demyelination
- Inflammatory Microglia in Degenerative Aging and Alzheimer's Disease
- Apolipoprotein E is a Longevity-Associated Gene
- Cellular Senescence in the Aging and Dysfunction of Skin
- Platelet Rich Plasma Treatment Rescues Damaged Salivary Gland Function in Aged Mice
- Methionine Restriction Extends Life in Flies
Should We Think of Rheumatoid Arthritis as an Age-Related Condition?
https://www.fightaging.org/archives/2024/01/should-we-think-of-rheumatoid-arthritis-as-an-age-related-condition/
There are medical conditions that occur only in old age, and there are medical conditions, such as cancer, that can occur at any point in life, but more so in the old. Then there are grey area conditions that may occur to some greater degree in later life, or be worse in later life, but this is by no means widely appreciated. Where does the autoimmune condition of rheumatoid arthritis sit in this spectrum? Unlike cancer, it is not commonly thought of as an age-related disease, even though it is certainly affected and made worse by the processes of aging. This point is discussed in today's open access commentary and the paper to which it refers.
One of the more interesting aspects of this work is the background of poor mechanistic understanding that attends research into the treatment of rheumatoid arthritis. Despite considerable effort, it remains a poorly understood condition. The immune system is complex, and there as, as of yet, no very straightforward evidence for a specific malfunction of the immune system to trigger the condition. Available treatments take the form of quite blunt approaches to the suppression of chronic inflammatory dysfunction of the immune system, such as TNFα inhibition, and have meaningful long-term side-effects related to impairment of the necessary immune response to infection and damage.
Biological ageing: a promising target for prevention and management of rheumatoid arthritis
Researchers have used US National Health and Nutrition Examination Survey and UK Biobank to show that people with accelerated biological ageing had an increased risk of rheumatoid arthritis compared with people without accelerated biological ageing. Accelerated biological ageing particularly increased the risk among people with a high genetic predisposition for rheumatoid arthritis, suggesting a joint effect on the risk of incident disease. The life expectancy at age 45 years of people with both rheumatoid arthritis and accelerated biological ageing was 2.4-5.7 years lower than that of people with rheumatoid arthritis who did not have accelerated biological ageing. The findings support the significant effects of biological ageing on the development and progression of rheumatoid arthritis.
The pathogenesis of accelerated biological ageing in rheumatoid arthritis is complex and not fully understood. The high prevalence of comorbidities and associated polypharmacy in rheumatoid arthritis is a potential pathway by which biological ageing is accelerated and life expectancy is reduced. Besides the genetic factors associated with rheumatoid arthritis, molecular mechanisms, including epigenetic modifications and telomere attrition, are interrelated with biological ageing and thus might increase susceptibility to rheumatoid arthritis. Regarding immune ageing, T cells are particularly susceptible to ageing-related changes. Treatment with biological and targeted synthetic disease-modifying antirheumatics might be effective in restoring the functional intactness of aging T cells in rheumatoid arthritis. Since the advent of these drugs, life expectancy and quality of life have increased in patients with rheumatoid arthritis. Whether these drugs have a favourable effect on biological ageing in rheumatoid arthritis should be investigated.
Life expectancy is a key indicator reflecting the mortality associated with a disease. Diverging from previous research that primarily focused on the effects of novel treatments, this study has shifted attention to an important and potentially reversible factor: loss of life expectancy resulting from accelerated biological ageing. Notably, the authors found that the absolute loss in life expectancy attributed to ageing characteristics did not differ significantly across age groups. These results suggest that the effects of reducing or reversing accelerated biological ageing on increasing life expectancy could be similar across different age groups, highlighting the importance of management of biological ageing at every life stage. Thus, controlling biological ageing could be an effective way to enhance quality of life and extend the lifespan of people with rheumatoid arthritis, irrespective of chronological age. However, given that rheumatoid arthritis primarily affects women and the inherent sex-based differences in life expectancy and in the speeds and processes of ageing, it remains unclear whether accelerated biological ageing affects life expectancy differently for men and for women with rheumatoid arthritis. Therefore further investigation is needed.
Failing Mitochondrial Quality Control in Aging and Neurodegeneration
https://www.fightaging.org/archives/2024/01/failing-mitochondrial-quality-control-in-aging-and-neurodegeneration/
Every one of our cells contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now fully integrated into our biochemistry. Mitochondria contain their own small remnant genome, the mitochondrial DNA, replicate like bacteria, and toil to produce adenosine triphosphate (ATP), a chemical energy store molecule used to power cell processes. Mitochondrial function declines with age, unfortunately, and our cells suffer for it. This contributes meaningfully to many age-related conditions. This decline appears to result in large part from changes in gene expression that impair the various quality control processes that (a) ensure mitochondrial proteins are correctly formed, and (b) that damaged mitochondria are recycled. Those changes in gene expression are maladaptive responses to other aspects of aging, perhaps in part the shift to an inflammatory environment, perhaps in part due to changes in nuclear structure resulting from cycles of double strand DNA repair, and so forth.
The search for ways to improve mitochondrial function in old age is an area of considerable focus in the aging research community and longevity industry. Partial reprogramming is perhaps the most well funded approach, but numerous efforts are being undertaken to find ways to improve mitochondrial quality control to greater degrees than can be achieved via supplements and exercise. Beyond this, a number of groups are building the infrastructure needed to manufacture large amounts of mitochondria for transplantation. This latter approach seems the most viable path if the goal is near term success; researchers have demonstrated that mitochondrial can be delivered into tissues and taken up to improve cell function. It is just a matter of being able to cost-effectively manufacture very large numbers of these organelles.
Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases
Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function.
In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
Is Alternative Splicing a Meaningful Cause of Degenerative Aging, or Largely a Downstream Side-Effect?
https://www.fightaging.org/archives/2024/01/is-alternative-splicing-a-meaningful-cause-of-degenerative-aging-or-largely-a-downstream-side-effect/
A gene sequence consists of a mix of shorter sequences, only some of which are used to manufacture the protein encoded in that gene. Exon sequences are included and intron sequences are excluded. Nothing is ever quite that simple, of course, but changes in which exons and introns end up in a protein enable multiple proteins to be produced from a single gene sequence. Sometimes this is an accident, assome genes are prone to accidental production of truncated or extended proteins that are toxic. Sometimes this is an evolutionary reuse in which a gene produces several different vital proteins with quite different functions.
The process by which a gene sequence is interpreted to manufacture messenger RNA (mRNA) molecules for a given protein (some or all exons, none of the introns) is called RNA splicing. Alternative splicing is what happens when the dominant protein is not produced, but rather some other protein is made instead. Splicing is a complex and highly regulating process, and like all such processes in the cell, it runs awry with age. Changes in the gene expression of splicing factors and other forms of change and damage in the cell can alter the distribution of different mRNAs produced from a given gene, or lead to a greater production of malformed, toxic proteins.
As for all of the changes taking place in the machinery of gene expression, we might well ask where alternative splicing fits into the complex web of interacting causes and consequences of degenerative aging. Are these changes closer to being a root cause of aging, with many harmful downstream effects resulting from disruption of RNA splicing? Or are these changes far downstream, with little further damage and dysfunction resulting from dysregulated RNA splicing? There is a sea of data, but it remains hard to argue for a given position without acknowledging the surplus of evidence that supports all of the other positions. For what it is worth, methods of slowing aging tend to correlate with lesser disruption of RNA splicing. The most interesting research here is by groups like SENISCA that are attempting to restore youthful organization of RNA splicing, and have achieved some success on this front. It remains to be seen as to how this will turn out, given that it remains a comparatively new area of research and development.
Age-Related Alternative Splicing: Driver or Passenger in the Aging Process?
A wide range of changes in cellular mechanisms involving both transcriptional and post-transcriptional regulation have been linked to normal aging. While age-related variations in the cellular environment lead to eventual molecular changes, it is also possible that the molecular changes accelerate aging and age-related disorders (ranging from hypertension to cardiovascular disease, cancer, and neurodegeneration). Furthermore, different tissues and organs may experience different age-related alterations in transcriptional and post-transcriptional regulation. In higher eukaryotic genomes, alternative splicing (AS) of both protein and non-coding genes not only profoundly contributes to increasing the functional diversity and complexity of the whole transcriptome, but it also seems to be a master regulator of cellular and individual aging.
Although the majority of variations in alternative splicing events occur during development, it is estimated that approximately 30% of all alternative splicing alterations occur during aging. As rodents and humans consistently exhibit age- and tissue-related variations in the expression of genes involved in splicing, age-related changes in splicing may be caused by the age-related decline in splicing factor expression. On the other hand, the main categories of genes with age-related altered splicing include those encoding genes with neuronal-specific activities such as synaptic transmission in the human brain, as well as those implicated in collagen production and post-translational modification in the human Achilles tendon. These observations suggest that age-dependent splicing changes are more likely to occur in at least some of the same categories of tissue-specific genes that show transcriptional decline with aging.
Aging-dependent splicing alterations can explain why some genes show a tissue-specific decrease in expression. Splicing errors during pre-mRNA processing can result in the incorrect usage of alternative splice sites, leading to intron retention in the mature mRNA transcript rather than proper exon joining. Intron retention introduces premature termination codons that target the aberrant transcripts for degradation through nonsense-mediated decay (NMD). This differs from frameshift mutations caused by small insertions or deletions during splicing, which can also introduce premature stop codons but do not always trigger transcript degradation by NMD, and may allow some protein production from the altered transcripts.
The interplay between splicing and aging has major implications for aging biology, though differentiating correlation and causation remains challenging. Declaring a splicing factor or event as a driver requires comprehensive evaluation of the associated molecular and physiological changes. A greater understanding of how RNA splicing machinery and downstream targets are impacted by aging is essential to conclusively establish the role of splicing in driving aging, representing a promising area with key implications for understanding aging, developing novel therapeutic options, and ultimately leading to an increase in the healthy human lifespan.
Sirtuin 2 Overexpression Fails to Extend Life in Mice
https://www.fightaging.org/archives/2024/01/sirtuin-2-overexpression-fails-to-extend-life-in-mice/
One long-lasting result of the hype engineered over sirtuin 1 overexpression as a possible avenue to modestly slow aging is a continued focus on other sirtuins in the context of aging. Sirtuin 1 overexpression turned out to be entirely unimpressive, a dead end. Sirtuin 6, however, is more interesting, and overexpression in mice does modestly extend life span, possibly by improving DNA repair efficiency. It may also be the case that sirtuin 3 overexpression can improve mitochondrial function to a great enough degree to also be interesting.
On the whole, however, this sort of approach to manipulating metabolism has yet to produce gains in mouse life span that come close to that achieved by calorie restriction. And gains in mouse life span dwindle when the same strategies are applied to longer-lived species, in which evolution has already implemented many of the gains that can be achieved in short-lived species. Still, the research community continues down this road, and sirtuins remain on the agenda. That leads to studies such as the one reported in today's open access paper, in which researchers rule out sirtuin 2 upregulation as an area of interest.
SIRT2 transgenic over-expression does not impact lifespan in mice
The sirtuin NAD+-dependent deacylase family of enzymes contains seven members, playing diverse roles in epigenetic regulation, DNA repair, and metabolic homeostasis. Interest in these proteins was sparked by initial findings on the role of Sir2 in yeast replicative lifespan, and subsequent interest in the mammalian homologue SIRT1. This was further compounded by the identification of small molecule allosteric activators for SIRT1, with these compounds demonstrating potential in preclinical models of disease. Whole-body transgenic over-expression of SIRT1 impacts some aspects of late-life health, it does not increase overall lifespan in mice, unlike the transgenic over-expression of another nuclear sirtuin, SIRT6. This may be complicated by tissue specific effects, as unlike whole-body overexpression, tissue specific SIRT1 overexpression in the hypothalamus results in increased overall lifespan. It is currently unknown whether altered activity of other members of this family can impact mammalian ageing.
One member of this family, sirtuin-2 (SIRT2) was previously found to regulate stability of BubR1, which has been implicated in maintaining accurate chromosome segregation during mitosis to prevent cellular senescence during ageing. Transgenic over-expression of BubR1 extends lifespan, while its under-expression results in the accelerated onset of age-related pathologies and shortened overall lifespan. Previously, we showed that SIRT2 transgenic over-expression (SIRT2-Tg) in the context of BubR1 under-expression partially rescued the lifespan of male, but not female mice. Further, we showed that this same SIRT2-Tg allele on a non-progeroid wild-type (WT) C57BL6 background could delay reproductive ageing in mice, with an extended period of functional fertility.
While members of the sirtuin family have been classically studied as NAD+-dependent deacetylase enzymes, SIRT2 is also capable of removing other acyl modifications on lysine residues, including lactylation, crotonylation, myristoylation, and benzoylation. Well-studied substrates for SIRT2 include tubulin, histones, glucose-6phospohate dehydrogenase (G6PD), Foxo1, Foxo3a, p65, IDH1, APCCDH1 and others. SIRT2 has been proposed as a therapeutic target in neurodegenerative disease, though a number of these findings are contradictory. For example, SIRT2 inhibitors can provide neuroprotection against models of Huntington's disease, Alzheimer's disease, and Parkinson's disease; however, SIRT2 deletion impairs axonal energy metabolism, resulting in locomotor disability, with SIRT2 also playing a putative role in reducing neuroinflammation. Similarly, there is evidence for SIRT2 as both a suppressor and promoter of tumour growth, though these roles are likely to be context dependent.
Given this previous work, the aim of this investigation was to establish whether SIRT2 could impact overall lifespan on a non-progeroid background in mice. Here, we characterized aspects of metabolism, development, motor coordination, mitochondrial function, bone health, fertility and overall lifespan in a previously described mouse strain over-expressing SIRT2. While SIRT2 over-expression had impacts on levels of certain metabolites in the brain, we found no impact of SIRT2 overexpression any aspect of overall health or lifespan, suggesting that levels of this protein are not relevant to functional biological ageing and lifespan under standard, non-progeroid conditions.
Standardization to a Single Epigenetic Clock is Much Overdue
https://www.fightaging.org/archives/2024/01/standardization-to-a-single-epigenetic-clock-is-much-overdue/
In the past year or two, a great deal of effort on the part of leading researchers has gone into trying to standardize the use of a single epigenetic clock based on DNA methylation status of CpG sites on the genome. Suitable candidate universal mammalian clocks now exist. There are good reasons for standardization. Given that any large amount of omics data can be used to produce aging clocks, where "clock" in this context means a weighted combination of measured values that correlates well with chronological age or biological age, there is an essentially infinite number of potential clocks. People can build or cherry pick clocks that are optimized to produce large numbers for their specific therapeutic approach to age-slowing or age-reversing intervention. Further, comparing results obtained with different clocks is essentially impossible. This leads to wasted effort.
As an example of why standardization is important, we might look at today's open access paper, in which researchers pick a clock that isn't one of the proposed standards, uses only four CpG sites (a tiny number!) and show large differences between study groups. One wonders if they picked the clock because the numbers are large. One can't really do anything to compare this data with data obtained from different clocks: this paper is thus unlikely to contribute meaningfully to the advance of knowledge. Further, we should probably assume that any epigenetic clock built using such a small number of CpG sites is reflecting only a very narrow slice of the full panoply of processes of degenerative aging. It is reasonable to think that no such clock will be able to usefully assess the results of interventions that target only a subset of the processes of aging. All in all, this isn't helpful.
Decelerated Epigenetic Aging in Long Livers
Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being studied worldwide as an example of successful aging due to their longevity. We used Bekaert's blood-based age prediction model to estimate the epigenetic age of 50 conditionally "healthy" and 45 frail long-livers over 90 years old. Frailty assessment in long-livers was conducted using the Frailty Index. The control group was composed of 32 healthy individuals aged 20-60 years.
The DNA methylation status of the 4 CpG sites (ASPA CpG1, PDE4C CpG1, ELOVL2 CpG6, and EDARADD CpG1) included in the epigenetic clock was assessed through pyrosequencing. According to the model calculations, the epigenetic age of long-livers was significantly lower than their chronological age (on average by 21 years) compared with data from the group of people aged 20 to 60 years. This suggests a slowing of epigenetic and potentially biological aging in long livers.
At the same time, the obtained results showed no statistically significant differences in delta age (difference between the predicted and chronological age) between "healthy" long livers and long livers with frailty. We also failed to detect sex differences in epigenetic age either in the group of long livers or in the control group. It is possible that the predictive power of epigenetic clocks based on a small number of CpG sites is insufficient to detect such differences. Nevertheless, this study underscores the need for further research on the epigenetic status of centenarians to gain a deeper understanding of the factors contributing to delayed aging in this population.
It is Never Too Late to Improve Health by Reducing Calorie Intake
https://www.fightaging.org/archives/2024/01/it-is-never-too-late-to-improve-health-by-reducing-calorie-intake/
Life lived on a comparatively high calorie diet is both shorter and less healthy than a life lived on a comparatively lower calorie diet, so long as one still obtains all of the necessary micronutrients needed to avoid malnutrition. This is clearly the case in near all species in which the outcome of calorie restriction has been assessed. Human trials of even modest calorie restriction have demonstrated a panoply of improvements to long term health. A great deal of overfeeding and calorie restriction research is conducted in short-lived species, however, such as the study here in flies. The principle remains the same, though: it is never too late to try a lower intake of calories as a lifestyle choice intended to improve health.
Many animal studies have shown that eating less - meaning sharply restricting calories without malnutrition - lengthens lifespan. While human trials have shown evidence of beneficial effects of eating less on health, especially in healthy obese individuals, studies examining effects on lifespan have been unrealistic for humans.
Fruit flies live short and fast - the lifespan of flies raised on a high calorie diet is less than 80 days, while the longest lived on a low calorie diet can reach 120 days. In this study, researchers looked specifically at male flies. Young flies switched from a high calorie to a low-calorie diet at 20 days old lived very long lives, similar to the flies fed a low-calorie diet from day one. What surprised the researchers was that switching the flies' diet to a low calorie one remained a reliable way to extend lifespan even for old flies in ill health. The older insects raised on the high calorie diet had more lipids in their bodies, and they expended more energy defending their bodies from reactive oxygen species. They also had a higher death rate than flies raised on the low-calorie diet. But when the surviving high calorie flies were switched to a low-calorie diet at 50 or even 60 days (when most of the high calorie flies had already died) their metabolisms changed, their death rate plummeted, and their lifespans lengthened.
The team's results show that flies' metabolisms can adapt to a change in diet even in old age. Since many basic metabolic pathways in fruit flies are shared with humans, this study suggests that human metabolism may respond the same way, and individuals eating a high calorie diet could benefit from reducing their calorie intake at old age. The researchers are currently analyzing data from female fruit flies to see if there are any sex-related differences in response to diet shifting.
Air Pollution Implicated as a Contributing Cause of Numerous Age-Related Conditions
https://www.fightaging.org/archives/2024/01/air-pollution-implicated-as-a-contributing-cause-of-numerous-age-related-conditions/
A compelling range of evidence links greater particulate air pollution to a greater incidence of age-related disease and mortality. The primary mechanism is considered to be induction of chronic inflammation via the interaction of particulates with lung tissue. Constant, unresolved inflammatory signaling is disruptive to cell and tissue function throughout the body, accelerating the onset and progression of all of the most common disabling and ultimately fatal age-related conditions.
Growing evidence suggests that exposure to fine particulate matter (PM2.5) may reduce life expectancy; however, the causal pathways of PM2.5 exposure affecting life expectancy remain unknown. Here, we assess the causal effects of genetically predicted PM2.5 concentration on common chronic diseases and longevity using a Mendelian randomization (MR) statistical framework based on large-scale genome-wide association studies (GWAS) employing a total of more than 400,000 participants.
After adjusting for other types of air pollution and smoking, we find significant causal relationships between PM2.5 concentration and angina pectoris, hypercholesterolaemia, and hypothyroidism, but no causal relationship with longevity. Mediation analysis shows that although the association between PM2.5 concentration and longevity is not significant, PM2.5 exposure indirectly affects longevity via diastolic blood pressure (DBP), hypertension, angina pectoris, hypercholesterolaemia and Alzheimer's disease, with a mediated proportion of 31.5%, 70.9%, 2.5%, 100%, and 24.7%, respectively. Our findings indicate that public health policies to control air pollution may help improve life expectancy.
Aptamers to Reduce Inflammatory AGE-RAGE Interaction
https://www.fightaging.org/archives/2024/01/aptamers-to-reduce-inflammatory-age-rage-interaction/
Researchers here discuss the use of aptamers that can bind to advanced glycation endproducts (AGEs). This prevents the AGEs from themselves binding to the receptor for AGEs (RAGE), an interaction that provokes inflammation. A sizable presence of circulating, short-lived AGEs is characteristic of the abnormal metabolism of obesity and obesity-related conditions such as type 2 diabetes. It is an open question as to how much of a contribution to the chronic inflammation of aging is provided by AGEs in people of a normal weight, eating a basically sensible diet, however. The only way to find out is to test a therapy of this nature, in which only the contribution of AGEs is suppressed, and then observe the results.
As AGEs have been considered a promising target for therapeutic intervention in various diseases, a large number of compounds have been proposed as AGE formation inhibitors or AGE-RAGE interaction blockers. However, owing to their limited efficacy or potential adverse side effects in vivo, none of these compounds have reached clinical application. DNA aptamers are short single-stranded DNA sequences that can selectively bind to target molecules. Compared with protein antibodies, DNA aptamers have several advantages, including short generation time, low costs of manufacturing, no batch-to-batch variability, and high modifiability and thermal stability. RNA aptamers that can inhibit vascular endothelial growth factors are clinically approved for the treatment of age-related macular degeneration, and a number of aptamers have entered clinical trials, including for ocular diseases, hematologic diseases, and cancer. Recently, we have innovatively developed DNA aptamers raised against AGEs (AGE-Apts) that can inhibit the toxic effects of AGEs.
We herein evaluated the effects of AGE-Apts on muscle mass and strength in senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old male SAMP8 mice received subcutaneous infusion of control DNA aptamers (CTR-Apts) or AGE-Apts. Mice in an age-matched senescence-accelerated mouse resistant strain 1 (SAMR1) group were treated with CTR-Apts as controls. The soleus muscles were collected after the 8-week intervention for weight measurement and histological, RT-PCR, and immunofluorescence analyses. Grip strength was measured before and after the 8-week intervention.
AGE-Apt treatment inhibited the progressive decrease in the grip strength of SAMP8 mice. SAMP8 mice had lower soleus muscle weight and fiber size than SAMR1 mice, which was partly restored by AGE-Apt treatment. Furthermore, AGE-Apt-treated SAMP8 mice had a lower interstitial fibrosis area of the soleus muscle than CTR-Apt-treated SAMP8 mice. The soleus muscle levels of AGEs, oxidative stress, receptor for AGEs, and muscle ring-finger protein-1 were increased in the CTR-Apt-treated mice, all of which, except for AGEs, were inhibited by AGE-Apt treatment. Our present findings suggest that the subcutaneous delivery of AGE-Apts may be a novel therapeutic strategy for aging-related decrease in skeletal muscle mass and strength.
A Look at the Signaling that Produces Bystander Senescence
https://www.fightaging.org/archives/2024/01/a-look-at-the-signaling-that-produces-bystander-senescence/
The burden of senescent cells in tissues throughout the body increases with age, as the immune system becomes ever less capable of clearing such cells in a timely fashion. Senescent cells do not replicate, but instead devote their energies to the production of pro-growth, pro-inflammatory signaling that is disruptive to tissue structure and function when maintained for the long term. These cells actively contribute to degenerative aging in this way. Senescent cells are not just produced by reaching the Hayflick limit, or by damage of some sort. They can also become senescent in response to the signaling of other senescent cells, or via other forms of stress signaling that are far from fully understood at this time. Researchers here delve into what is know of the signaling that can produce what is known as bystander senescence.
Current data suggest that senescence is neither entirely intrinsic nor simply time-dependent. Certain soluble elements present in the systemic milieu - proteins, lipids, and reactive oxygen species (ROS) - can induce bystander senescence, but there are likely others, as yet unidentified, that are also capable of accomplishing this result, either individually or in combination. Extracellular vesicles (EVs) can induce bystander senescence, but only a few components of these vesicles that are responsible for this result are specifically known. Many of these components are microRNAs (miRNAs); however, hundreds of miRNAs have been identified, and we still have much to learn about their functions. Whether nuclear DNA or mitochondrial DNA in apoptotic bodies contributes to senescence in the healthy cells that engulf them is a tantalizingly unexplored frontier. The same is true for non-vesicular multi-component macromolecules that are known to be taken up by non-senescent cells. Our knowledge of the systemic components that provoke senescence in healthy cells remains incomplete, and the importance of this paradigm demands further investigation.
The characterization of age-altered contents - proteins, lipids, and nucleic acids - of vesicles and aggregates, as well as the identification of the senescent cells that release them and the mechanisms of their uptake, is an enormous but essential endeavor. A deeper understanding of this field will be invaluable to the development of senolytics that can prevent an organism-wide loss of health due to the propagation of senescence from a pathological tissue to healthier tissues. Notably, it is important to confirm the many in vitro studies using in vivo paradigms. In vivo studies will not only confirm the physiological relevance of senescence but also provide insights into whether senescence is induced directly by interactions between the inducing factor and the target cell or mediated indirectly by other cell types (e.g., macrophages and microglia) whose secretions may change when they are affected by the inducing factor. Moreover, it is necessary to employ multiple assays to reach reliable conclusions. When asserting that a cell is senescent, for example, this should be demonstrated by morphology, a lack of proliferation, an increase in cyclin-dependent kinase inhibitor production, senescence-assocated-β-gal, phosphorylated histone γH2AX, and a change in secretions, or a comparable set of assays appropriate to the cell type and senescence classification. Armed with such information, we should be able to develop new strategies that will inform us regarding physiological senescence, helping to ameliorate the adverse systemic effects of damaged tissues on an organism.
Calorie Restriction Mimetics as an Approach to Slow Demyelination
https://www.fightaging.org/archives/2024/01/calorie-restriction-mimetics-as-an-approach-to-slow-demyelination/
Myelin sheathes axons, the connections between neurons. This sheath is essential to nervous system function, and a range of unpleasant diseases result from loss of myelin, such as through the autoimmune activity of multiple sclerosis. Demyelination occurs to a lesser degree over the course of aging, the standard problem of a complex system becoming disarrayed as the result of various forms of molecular damage and maladaptive reactions to that damage. Here, as elsewhere, chronic inflammation appears to be a contributing cause. Calorie restriction is known to dampen chronic inflammation and favorably alter the behavior of cells such as microglia and astrocytes that might otherwise be promoting inflammatory signaling. Thus the panoply of calorie restriction mimetic drugs is also a topic of interest - though none of these recaptures more than a fraction of the effects of the actual practice of calorie restriction, more is the pity.
The dysfunction of myelinating glial cells, the oligodendrocytes, within the central nervous system (CNS) can result in the disruption of myelin, the lipid-rich multi-layered membrane structure that surrounds most vertebrate axons. This leads to axonal degeneration and motor/cognitive impairments. In response to demyelination in the CNS, the formation of new myelin sheaths occurs through the homeostatic process of remyelination, facilitated by the differentiation of newly formed oligodendrocytes. Apart from oligodendrocytes, the two other main glial cell types of the CNS, microglia and astrocytes, play a pivotal role in remyelination. Following a demyelination insult, microglia can phagocytose myelin debris, thus permitting remyelination, while the developing neuroinflammation in the demyelinated region triggers the activation of astrocytes.
Modulating the profile of glial cells can enhance the likelihood of successful remyelination. In this context, recent studies have implicated autophagy as a pivotal pathway in glial cells, playing a significant role in both their maturation and the maintenance of myelin. In this review, we examine the role of substances capable of modulating the autophagic machinery within the myelinating glial cells of the CNS. Such substances, called caloric restriction mimetics, have been shown to decelerate the aging process by mitigating age-related ailments, with their mechanisms of action intricately linked to the induction of autophagic processes.
Inflammatory Microglia in Degenerative Aging and Alzheimer's Disease
https://www.fightaging.org/archives/2024/01/inflammatory-microglia-in-degenerative-aging-and-alzheimers-disease/
Microglia, the innate immune cells of the central nervous system, can enter an aggressive, inflammatory state in response to the presence of molecular waste, inflammatory signaling, mitochondrial damage, and so forth. They can also become senescent, which is also a pro-inflammatory state. The aging brain, and particularly the brains of patients with neurodegenerative conditions, exhibit a state of chronic inflammation, producing dysfunction, cell stress, and cell death. It remains to be seen as to how effective anti-inflammatory therapies targeting microglia will be in the treatment of neurodegenerative conditions and the slowing of brain aging. Comparatively simple approaches already exist, such as the use of CSF1R inhibitors to clear existing maladaptive microglia and thereby allow a new population to emerge lacking the damage and inflammatory behavior of the preexisting cells. Time will tell as to their utility.
Current evidence demonstrates that human microglial cells are a hugely varied and heterogeneous population. Microglial heterogeneity is crucial for neurodegeneration, although at the moment it was demonstrated mainly in neurodegenerative mice models. These animal models can only partially clarify what happens in humans due to the fact that Alzheimer's disease (AD) is a proper human disease which is complex and related to both genetic and environmental factors, with a trajectory of evolution that is different and peculiar for each patient. Just think of the association recently demonstrated between imaging markers of microglial reaction and behavioral symptoms in Alzheimer's disease, which is certainly not transferable to mouse models. Thus, the role of microglia in human healthy aging and in AD presents multiple aspects, complex and interconnected.
Although there are huge differences between humans and rodents, mouse models have been very useful to shed light on the microglial role in AD. From our systematic review emerges that microglia have a fundamental role in removing phosphorylated tau protein and harmed synapses and in the phagocytosis and compaction of amyloid-β deposits. All these actions represent the protective aspects of microglia that are crucial to prevent neurodegeneration. This neuroprotective role may become less efficient with advancing age, primarily due to increased oxidative stress and mitochondrial dysfunction. Probably, the loss of efficiency of microglia and the accumulation of protein debris ends up determining a persistent mild inflammation. Therefore, in the brain areas where neurodegenerative phenomena are concentrated, possibly also associated with chronic hypoxia, a pathological context is created in which microglia lose their homeostatic role and become exhausted or dystrophic, otherwise they can become aggressive enhancing neurodegenerative phenomena and synapse loss.
Thus, microglia may contribute to the progression of AD pathology in two ways: through functional exhaustion, with less efficiency in the removal of metabolic waste, or through neurotoxic phenomena due to an excess level of inflammation. Arguably, physiological aging and the maintenance of a healthy brain depends on establishing a balance between the actions and reactions of microglia. These lines of evidence suggest that microglia play a pivotal role in the pathogenesis of AD.
Apolipoprotein E is a Longevity-Associated Gene
https://www.fightaging.org/archives/2024/01/apolipoprotein-e-is-a-longevity-associated-gene/
It remains unclear as to why apolipoprotein E (APOE) variants are associated with longevity in humans. The gene has a well-studied role in Alzheimer's disease, but the reasons why APOE variants are associated with aging remain to be determined. The most likely mechanisms involve (a) interactions with age-related disruptions of lipid metabolism, both in the brain and elsewhere, and (b) indirect effects on the inflammatory behavior of innate immune cells such as microglia. There are plenty of other interactions to further study, however, such as in bone tissue, or effects on the gut microbiome. As is often the case, a great deal of data exists, but making sense of that data lags far behind the ability to generate more of it.
The APOE variants, respectively ε2 ε3, ε4, and ε3r, are determined by four haplotypes at the APOE locus (19q13.32). These four APOE alleles are probably the most investigated variants in the human genome. Remarkably, the APOE exon 4 region, encompassing the ε2/ε3/ε4 allele variants, is a well-defined CpG islands-rich area. Moreover, the two common SNPs rs429358 and rs7412 are CpG-altering and modify the CpG content of this area. This APOE CpG island-rich area is a transcriptional enhancer with a specificity linked to the ε4 allele and cell-type.
A genetic association of APOE with both human longevity and Alzheimer's disease (AD) was found, but the mechanistic contribution of APOE in aging and long life is largely under investigation. APOE pleiotropic roles may be explained by its exceptional epigenetic properties. In the AD brain, these epigenetic changes could contribute to neural cell dysfunction. Additionally, DNA methylation modifications have been found on specific genes associated with AD pathology such as APOE. In the AD brain, it was shown that APOE CpG islands were differentially methylated in an APOE-genotype and tissue-specific way.
In the lipid metabolism pathophysiology, ApoE may be related with normal/pathological aging, while its function in CNS pathophysiology needs further clarification. In fact, in the CNS, there was about a quarter of total body cholesterol that may exert a significant impact on synaptic plasticity. With advancing age, cholesterol metabolism may modify, and its related brain changes may be associated with the pathophysiology of AD. So, in longevity and healthy aging, lipid and cholesterol maintenance are a critical factor also from an interventional point of view.
Studies on longevity and healthy aging are related because subjects who live longer tend to be healthier for a greater part of their lives. Healthy aging can be described as achieving older age maintaining intact cognition and/or mobility and without disabilities or multimorbidity. This last can be defined as the coexistence of two or more chronic diseases in the same subjects. The detrimental effects of the APOE ε4 allele on longevity could influence the probability of a long human lifespan. The APOE ε2 allele has a greater frequency in long-lived individuals than the ε4 allele. Thus, the main longevity factor is the APOE ε3/ε3 genotype. The greater frequency of the ε3 allele in older individuals and their offspring than in controls derives from the higher amount of the homozygous APOE ε3/ε3 genotype in comparison with the ε2/ε3 or ε3/ε4 genotypes
Cellular Senescence in the Aging and Dysfunction of Skin
https://www.fightaging.org/archives/2024/01/cellular-senescence-in-the-aging-and-dysfunction-of-skin/
A great deal of research and development effort is now focused on finding ways to reduce the contribution of senescent cells to degenerative aging. Initiatives range from fundamental research into the biochemistry of senescent cells to clinical trials of early senolytic therapies capable of selectively destroying senescent cells. A growing burden of senescent cells is a feature of all organs and tissues in the body, the skin included. Researchers here discuss what is known of the role of cellular senescence in aging and dysfunction of skin, and what might be done about it.
The skin is the largest organ of the human body, and the site where signs of aging are most visible. These signs include thin and dry skin, sagging, loss of elasticity, wrinkles, as well as aberrant pigmentation. The appearance of these features is accelerated by exposure to extrinsic factors such as ultraviolet (UV) radiation or pollution, as well as intrinsic factors including time, genetics, and hormonal changes.
At the cellular level, aging is associated with impaired proteostasis and an accumulation of macromolecular damage, genomic instability, chromatin reorganization, telomere shortening, remodelling of the nuclear lamina, proliferation defects and premature senescence. Cellular senescence is a state of permanent growth arrest and a key hallmark of aging in many tissues. Due to their inability to proliferate, senescent cells no longer contribute to tissue repair or regeneration. Moreover, senescent cells impair tissue homeostasis, promote inflammation and extracellular matrix (ECM) degradation by secreting molecules collectively known as the "senescence-associated secretory phenotype" (SASP).
Senescence can be triggered by a number of different stimuli such as telomere shortening, oncogene expression, or persistent activation of DNA damage checkpoints. As a result, these cells accumulate in aging tissues, including human skin. In this review, we focus on the role of cellular senescence during skin aging and the development of age-related skin pathologies, and discuss potential strategies to rejuvenate aged skin.
Platelet Rich Plasma Treatment Rescues Damaged Salivary Gland Function in Aged Mice
https://www.fightaging.org/archives/2024/01/platelet-rich-plasma-treatment-rescues-damaged-salivary-gland-function-in-aged-mice/
Dysfunction of the salivary gland is an underappreciated and unpleasant age-related condition. Researchers here demonstrate that injection of platelet rich plasma into the salivary gland can rescue function in old mice by promoting regrowth of lost cells, reducing inflammation, and reducing the burden of cellular senescence in this tissue. As noted in the paper, platelet rich plasma is fairly widely used in the regenerative medicine industry, and this sort of result in an animal model is one of the reasons why this is the case.
Saliva, synthesized and secreted by the salivary glands (SGs), plays an essential role in the oral cavity by maintaining oral homeostasis, protecting against infection, and promoting digestion. A dysfunction of the SG leads to xerostomia or dry mouth, sialadenitis or salivary gland inflammation, worsening of dental caries, and periodontal diseases. Furthermore, xerostomia reduces overall health or the quality of patient's life. Temporal xerostomia is caused by acute infection or dehydration. On the other hand, permanent xerostomia is caused by autoimmune inflammatory diseases such as Sjogren syndrome, radiation therapy in head and neck cancer patients, xerogenic medication, or aging.
Platelet derivatives such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and plasma rich in growth factor (PRGF), are used widely in different areas of regenerative medicine to enhance the wound healing processes. This study examined whether the local injection of the supernatant of activated PRP (saPRP) into the salivary gland (SG) could help prevent aging-induced SG dysfunction and explored the mechanisms responsible for the protective effects on the SG hypofunction.
Human salivary gland epithelial cells (hSGEC) were treated with saPRP or PRP after senescence through irradiation. The significant proliferation of hSGEC was observed in saPRP treated group compared to irradiation only group and irradiation + PRP group. Cellular senescence, apoptosis, and inflammation were significantly reduced in the saPRP group.
The SG function and structural tissue remodeling by the saPRP were investigated with naturally aged mice. The mice were divided into three groups: 3 months old (3 M), 22 months old (22 M), and 22 months old treated with saPRP (22 M + saPRP). Salivary flow rate and lag time were significantly improved in 22 M + saPRP group compared to 22 M group. The histologic examinations showed the significant proliferation of acinar cells in the SG of the 22 M + saPRP group. A decrease of senescence, apoptosis, and inflammation was observed by western blot in the 22 M + saPRP group.
Methionine Restriction Extends Life in Flies
https://www.fightaging.org/archives/2024/01/methionine-restriction-extends-life-in-flies/
A sizable fraction of the benefits to health and life span resulting from the practice of calorie restriction derive from regulatory systems that are triggered by nutrient sensing mechanisms focused on specific amino acids, primarily methionine. Thus a lowered dietary methionine intake produces health benefits even when overall calorie intake remains the same. This is well demonstrated in animal models, but not well tested in humans, despite the existence of low methionine medical diets. This may be because the medical diet are expensive, and it is neither straightforward nor easy to plan and eat a low methionine diet. Guides exist, but as a practical matter it is challenging to implement.
Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not known. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life only robustly extends lifespan.
MetR in young flies induces the expression of many longevity-related genes, including Methionine sulfoxide reductase A (MsrA), which reduces oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adulthood MetR. Our study highlights the age-dependency of the organismal response to specific nutrients and suggests that nutrient restriction during a particular period of life is sufficient for healthspan extension.