Fight Aging!

Blood clotting relies upon platelets and the reaction of those platelets to circumstances that indicate clotting is required: when suitably provoked platelets adhere to tissue, change shape, and bind to one another to form a clot. Platelets are essentially small slices of cell membrane and cytoplasm, shed by a specialized form of bone marrow cell called a megakaryocyte. Like all complex processes, clotting is impacted by age-related changes in cells and tissue. Platelets become more willing to clot, and can produce inappropriate clotting inside blood vessels, leading to thrombosis. We might ask how much of this problem is innate to platelets versus arising from damage to the vascular endothelium and an altered signaling environment.

In today's open access preprint, researcher suggest that the problem is innate to platelets. The authors provide evidence for a minority population of megakaryocytes to grow in number with age. This population produces overly reactive platelets, and as these problematic platelets grow as a proportion of all platelets, so the risk of inappropriate clotting rises. This is analogous to other similar issues in the production of blood cells and immune cells in the bone marrow, in which aging produces unfavorable shifts in relative numbers. Evidence to date suggests much of this is driven by chronic inflammation, but that is no doubt far from the only mechanism in play.

A rare HSC-derived megakaryocyte progenitor accumulates via enhanced survival and contributes to exacerbated thrombopoiesis upon aging

Distinct routes of cellular production from hematopoietic stem cells (HSCs) have defined our current view of hematopoiesis. Recently, we challenged classical views of platelet generation, demonstrating that megakaryocyte progenitors (MkPs), and ultimately platelets, can be specified via an alternate and additive route of HSC-direct specification specifically during aging. This "shortcut" pathway generates hyperactive platelets likely to contribute to age-related platelet-mediated morbidities.

Here, we used single-cell RNA/CITEseq to demonstrate that these age-unique, non-canonical (nc)MkPs can be prospectively defined and experimentally isolated from wild type mice. Surprisingly, this revealed that a rare population of ncMkPs also exist in young mice. Young and aged ncMkPs are functionally distinct from their canonical (c)MkP counterparts, with aged ncMkPs paradoxically and uniquely exhibiting enhanced survival and platelet generation capacity. We further demonstrate that aged HSCs generate significantly more ncMkPs than their younger counterparts, yet this is accomplished without strict clonal restriction.

Together, these findings reveal significant phenotypic, functional, and aging-dependent heterogeneity among the MkP pool and uncover unique features of megakaryopoiesis throughout life, potentially offering cellular and molecular targets for mitigation of age-related adverse thrombotic events.

One of the many interesting questions about Alzheimer's disease is why the relationship with being overweight or obese is tenuous in comparison to, say, type 2 diabetes. Why are there so many dramatically overweight people who do not develop Alzheimer's disease? As researchers here note, one can clearly point to Alzheimer's-adjacent mechanisms that obesity makes worse. Inflammatory dysfunction of the innate immune cells of the brain known as microglia has attracted a lot of attention in recent years, thought to contribute to all forms of neurodegeneration. Here, researchers look at one mechanism by which excess visceral fat tissue can harm microglia, giving rise to behaviors observed in the brains of Alzheimer's patients and animal models.

Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD.

RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity.

In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD.

Link: https://doi.org/10.1016/j.nbd.2024.106741

Forms of fasting and calorie restriction all function to produce sweeping, favorable alterations to metabolism. In short-lived animals, these changes significantly extend healthy life span. In long-lived animals, the effects on life span are more muted. The challenge in understanding the interaction between reduced calorie intake and pace of aging is that near everything changes in response to diet. There is no firm understanding at the detail level to link the copious observations into a coherent explanation of how aging is slowed. While evidence points to upregulation of autophagy as the primary mechanism connecting reduced calorie intake to slowed aging, it seems clear that researchers will still be writing papers like this one for decades yet.

Dietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short- and long-term use in C57BL/6 J mice.

We show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids, and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation.

Link: https://doi.org/10.1186/s12915-024-02061-2

Animal and human data make a compelling case for differences in the gut microbiome between individuals to contribute to variations in the pace of aging. There is an even better case for age-related changes in the relative proportions of microbial species making up the gut microbiome to accelerate degenerative aging, via loss of beneficial metabolite production and increased chronic inflammation, among other mechanisms. Most directly, fecal microbiota transplantation from young donors to old individuals produces a lasting rejuvenation of the gut microbiome that in turn improves health and extends life.

Straightforward analysis of human epidemiological data can only produce correlations between measures of health and outcomes such as mortality and disease risk. Mendelian randomization is a way to add known genetic influences on health into the mix in order to generate some support for causation from the epidemiological data. In today's open access paper, researchers apply this strategy to the correlations between gut microbiome composition and longevity in sizable human study populations. The evidence suggests that gut microbiome differences do influence long-term health and life expectancy, as one might expect from the more direct intervention studies in animals.

Mendelian randomization analyses support causal relationships between gut microbiome and longevity

The gut microbiome plays a significant role in longevity, and dysbiosis is indeed one of the hallmarks of aging. However, the causal relationship between gut microbiota and human longevity or aging remains elusive. Our study assessed the causal relationships between gut microbiome and longevity using Mendelian Randomization (MR). Summary statistics for the gut microbiome were obtained from four genome-wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340), Dutch Microbiome Project (N = 7738), German individuals (N = 8956), and Finland individuals (N = 5959). Summary statistics for Longevity were obtained from five GWAS meta-analysis, including Human healthspan (N = 300,447), Longevity (N = 36,745), Lifespans (N = 1,012,240), Parental longevity (N = 389,166), and Frailty (one of the primary aging-linked physiological hallmarks, N = 175,226).

Our findings reveal several noteworthy associations, including a negative correlation between Bacteroides massiliensis and longevity, whereas the genus Subdoligranulum and Alistipes, as well as species Alistipes senegalensis and Alistipes shahii, exhibited positive associations with specific longevity traits. Moreover, the microbial pathway of coenzyme A biosynthesis I, pyruvate fermentation to acetate and lactate II, and pentose phosphate pathway exhibited positive associations with two or more traits linked to longevity. Conversely, the TCA cycle VIII (helicobacter) pathway consistently demonstrated a negative correlation with lifespan and parental longevity. Our findings of this MR study indicated many significant associations between gut microbiome and longevity. These microbial taxa and pathways may potentially play a protective role in promoting longevity or have a suppressive effect on lifespan.

In aged cells, mitochondrial dysfunction leads to mislocalization of mitochondrial DNA fragments to the cytosol. There, innate immune defenses such as the cGAS-STING pathway react to the mitochondrial DNA in much the same way as they would react to bacterial or viral sequences, provoking inflammatory signaling. This is a bad thing, a maladaptive response that contributes to age-related disease and loss of function. Here, researchers show that this chronic stimulation of the cGAS-STING pathway degrades the normal, useful response of STING to the presence of pathogens, thereby contributing to the age-related loss of immune defenses against infection. This theme, chronic inflammation interfering in useful short-term inflammatory responses, is seen throughout the aged immune system.

Ageing is a major risk factor that contributes to increased mortality and morbidity rates during influenza A virus (IAV) infections. Macrophages are crucial players in the defense against viral infections and display impaired function during ageing. However, the impact of ageing on macrophage function in response to an IAV infection remains unclear and offers potential insight for underlying mechanisms. In this study, we investigated the immune response of young and aged human monocyte-derived macrophages to two different H1N1 IAV strains.

Interestingly, macrophages of aged individuals showed a lower interferon response to IAV infection, resulting in increased viral load. Transcriptomic data revealed a reduced expression of stimulator of interferon genes (STING) in aged macrophages albeit the cGAS-STING pathway was upregulated. Our data clearly indicate the importance of STING signaling for interferon production. Evaluation of mitochondrial function during IAV infection revealed the release of mitochondrial DNA to be the activator of cGAS-STING pathway. The subsequent induction of apoptosis was attenuated in aged macrophages due to decreased STING signaling.

Our study provides new insights into molecular mechanisms underlying age-related immune impairment. To our best knowledge, we are the first to discover an age-dependent difference in gene expression of STING on a transcriptional level in human monocyte-derived macrophages possibly leading to a diminished interferon production.

Link: https://doi.org/10.1186/s12979-024-00482-9

The idea that there are portions of the world in which lifestyle choice is leading to a sizable increase in life expectancy for large numbers of people, known as Blue Zones, is increasingly looking to be a mirage, the result of bad data and insufficiently skeptical analysis of that bad data. People are fascinated by longevity, credulous in the face of determined marketing, and Blue Zones have expanded as a cultural concept far beyond the limited evidence for their existence. People will be selling the Blue Zone concept long after the scientific community has written it off as one of many historical errors in epidemiology.

Researchers have spent years identifying what are claimed to be methodological errors throughout the longevity literature. For Blue Zones, the main argument is that a significant proportion of supposed centenarians may simply not exist. Around 1900, when the U.S. started to issue birth certificates, the number of centenarians aged 110 or older dropped sharply - presumably because people had been misrecording their age, whether on purpose or accidentally. Similarly, after the Greek government began checking on people receiving pensions, about 70% of all alleged centenarians in the country turned out to be dead. Researches also found that some age databases contain unusual numbers of people born on the first day of the month or on dates divisible by five, suggesting many of these birth dates are fabricated.

It is no coincidence that blue zones are found in poor, remote places that may have spotty record keeping. One can further argue that the supposed healthy lifestyle of the people who live in blue zones is not always backed up by real world data. For example, out of 47 Japanese prefectures, Okinawa ranks first on body mass index, second on beer consumption, and fourth on suicide rate among people over the age of 65.

"If equivalent rates of fake data were discovered in any other field - for example, if 82% of people in the UK Biobank or 17% of galaxies detected by the Hubble telescope were revealed to be imaginary - a major scandal would ensue. In demography, however, such revelations seem to barely merit citation. What demographers call validation is actually just checking the consistency of documents. If documents are consistently wrong then errors are not detectable."

Link: https://www.science.org/content/article/do-blue-zones-supposed-havens-longevity-rest-shaky-science

In order to achieve meaningful progress in our lifetimes, the future of cancer therapy must become driven by a focus on common features that occur in all or near all cancers, and which are fundamental to the biology of cancer. Approaching the biochemistry of cancer in any other way leads to therapies that are only relevant to a small fraction of all cancers, targeting mechanisms that a tumor cell population is quite capable of evolving away from, given the selection pressure applied by the treatment. There are only so many researchers and only so much research funding. To find success in controlling cancer as a class of disease, future cancer therapies must have the potential to be very broadly applicable, to need minimal changes or no changes in delivery to target different forms of cancer.

Cancerous cells replicate rapidly. Biochemical differences in cancer cells that are an inevitable consequence of a fast pace of replication seem likely to be a fruitful place to look for ways to attack the more severe forms of cancer. In today's research materials, scientists discuss one of these line items, which is that cells require copper to function, but cancerous cells deplete their copper reserves as a result of rampant replication. Finding ways to temporarily further deplete the available copper in cancerous cells can lead to their destruction. It is a simple concept, but as noted here, has proven to be challenging to implement in practice.

Tumor Cells Suffer Copper Withdrawal

While toxic in high concentrations, copper is essential to life as a trace element. Because cancer cells grow and multiply much more rapidly, they have a significantly higher need for copper ions. Restricting their access to copper ions could be a new therapeutic approach. The problem is that it has so far not been possible to develop drugs that bind copper ions with sufficient affinity to "take them away" from copper-binding biomolecules.

Researchers have now successfully developed such a system. At the heart of their system are the copper-binding domains of the chaperone Atox1. The team attached a component to this peptide that promotes its uptake into tumor cells. An additional component ensures that the individual peptide molecules aggregate into nanofibers once they are inside the tumor cells. In this form, the fiber surfaces have many copper-binding sites in the right spatial orientation to be able to grasp copper ions from three sides with thiol groups (chelate complex). The affinity of these nanofibers for copper is so high that they also grab onto copper ions in the presence of copper-binding biomolecules. This drains the copper pools in the cells and deactivates the biomolecules that require copper. As a consequence, the redox equilibrium of the tumor cell is disturbed, leading to an increase in oxidative stress, which kills the tumor cell.

Chaperone-Derived Copper(I)-Binding Peptide Nanofibers Disrupt Copper Homeostasis in Cancer Cells

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death.

The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells, impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.

Any sufficiently complex set of biological data can be used to build an aging clock via machine learning techniques, finding combinations of parameters that correlate with biological age, mortality, disease risk, and other outcomes. Phenotypic clocks use measures such as physical performance and clinical chemistry, while epigenetic clocks use DNA methylation or other epigenetic marks. New clocks of all sorts are being produced at a fair pace these days, while some groups are pushing for standardization to some of the better explored epigenetic clocks. Here find a review of the present landscape of phenotypic and epigenetic clocks, while noting that there are many other forms of clock beyond just these: transcriptomic, proteomic, and so forth.

Aging is the leading driver of disease in humans and has profound impacts on mortality. Biological clocks are used to measure the aging process in the hopes of identifying possible interventions. Biological clocks may be categorized as phenotypic or epigenetic, where phenotypic clocks use easily measurable clinical biomarkers and epigenetic clocks use cellular methylation data. In recent years, methylation clocks have attained phenomenal performance when predicting chronological age and have been linked to various age-related diseases. Additionally, phenotypic clocks have been proven to be able to predict mortality better than chronological age, providing intracellular insights into the aging process.

This review aimed to systematically survey all proposed epigenetic and phenotypic clocks to date, excluding mitotic clocks (i.e., cancer risk clocks) and those that were modeled using non-human samples. We reported the predictive performance of 33 clocks and outlined the statistical or machine learning techniques used. We also reported the most influential clinical measurements used in the included phenotypic clocks. Our findings provide a systematic reporting of the last decade of biological clock research and indicate possible avenues for future research.

Link: https://doi.org/10.18632/aging.206098

A fair sized body of evidence shows that physical activity improves memory function, both in the short term immediately following exercise, and over the long term for people engaging in regular exercise. This occurs in both younger and older people; it isn't just a matter of compensating for the effects of aging. The brain operates at the edge of its capacity, and delivery of greater nutrients and oxygen via increased cerebral blood flow following exercise enables greater activity. Thus it isn't surprising to see associations between memory function and the level of physical activity required to be an athlete. Of note, this study isn't all that great for older demographics - older athletes are relatively small in number.

This meta-analysis investigated the differences in working memory (WM) performance between athletes and non-athletes in non-sports-specific tasks. A comprehensive evaluation of 21 studies encompassing different age groups, genders, and sports types identified a small but statistically significant advantage in WM accuracy or capacity for athletes compared to non-athletes. Notably, this advantage was more pronounced when athletes were contrasted with a sedentary population.

We conducted seven subgroup analyses as part of this study. An age-specific investigation revealed a small but significant advantage in WM for young adult athletes over non-athletes. However, our investigation into the link between sports expertise and WM across various age groups is limited by a lack of substantial research focusing on older adults and children. Therefore, we are unable to confirm whether older athletes exhibit superior WM enhancement in comparison to other demographic groups. Considering the benefits of exercise for mitigating age-related cognitive decline, as well as its role in improving cognitive and learning abilities during childhood and adolescence, studies focusing on these age groups would be important. In particular, studies on older adults who are ex-athletes could provide insights into the long-term effects of sports.

Subgroup analysis based on sports types revealed that athletes from individual sports outperformed non-athletes in experimental WM tasks, while athletes from team sports showed no such significant advantage. Contrary to our expectations, no significant difference was found between individual and team sports subgroups in WM performance. These results suggest that the cognitive gains afforded by engaging in sports likely arise from general physiological and psychological effects.

Our comparison of WM performance of elite and non-elite athletes with that of non-athletes identified a WM advantage for elite athletes, while the advantage for non-elite athletes approached but did not reach statistical significance. Additionally, there was no significant difference in WM performance between the two subgroups. This finding prompts introspection regarding the sports performance-cognition nexus. Our results imply that cognitive benefits, particularly with respect to WM, stem more from sustained engagement in workout than from the high competitive level achieved.

The WM advantage observed in athletes in comparison to non-athletes is likely based on both physiological and psychological mechanisms. Physiologically, sports confer efficiency advantages in information processing and cognitive function by increasing cerebral blood flow, triggering the release of brain-derived neurotrophic factor, and promoting neural network plasticity. Psychologically, sports confer benefits that optimise cognitive performance through improved control, enhanced attention allocation, and accelerated information processing.

Link: https://doi.org/10.1080/09658211.2024.2423812

The composition of the gut microbiome, the specific microbial species that are present and their numbers relative to one another, varies from individual to individual and appears to influence health significantly, perhaps to a similar degree as lifestyle choices regarding diet and exercise. Further, the composition of the gut microbiome shifts with age in harmful ways, reducing the number of microbes that produce beneficial metabolites such as butyrate, while increasing the number of microbes that act to provoke an ever greater inflammatory reaction from the immune system. The chronic inflammation of aging is disruptive to tissue structure and function throughout the body, and in this way a poor gut microbiome can accelerate the onset and progression of age-related conditions and mortality.

The relationship between the gut microbiome and immune system is bidirectional. The immune system gardens the gut microbiome, so the aging of the immune system allows problematic microbes to grow in number. But equally, the aged gut microbiome can negatively affect the immune system. Today's open access paper looks at one of the ways in which this can happen, by accelerating the atrophy of active tissue in the thymus, a process known as thymic involution. The thymus is a small organ near the heart. Its primary function is to host the maturation of thymocytes produced in the bone marrow; these cells migrate to the thymus and undergo a process of selection to become T cells of the adaptive immune system. As the thymus atrophies with age, the supply of new T cells declines. With reinforcements, the adaptive immune system becomes ever more dysfunctional over time, populated by senescent, exhausted, and malfunctioning T cells.

Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing

The epithelium of the gastrointestinal tract represents the largest mucosal lining in the body that effectively limits the permeation of luminal microorganisms, antigens, and toxins through its paracellular space, a process that is regulated by intercellular tight junctions. Advancing age is accompanied by physiological changes to the intestine, including mucus layer thinning and remodelling of intestinal epithelial tight junction proteins, which contribute towards the breakdown of intestinal barrier function. This permits commensal bacteria and their products, such as lipopolysaccharide, from the gut lumen into the bloodstream (referred to as a leaky gut). Age-related intestinal barrier dysfunction is closely linked to the progressive deterioration of systemic health and the gradual appearance of metabolic defects. Moreover, recent evidence from animal studies indicates that it is a major contributor to low-grade systemic inflammation, termed inflammaging. Human intestinal barrier dysfunction, determined by elevated circulating lipopolysaccharide-binding protein (LBP) levels, is also associated with impaired physical function and inflammaging in healthy aged adults; highlighting the importance of investigating the role of intestinal barrier dysfunction in ageing.

Concurrently with changes to intestinal homeostasis, ageing is accompanied by remodelling of the immune system that attenuates the host's ability to mount robust immune responses, resulting in an immunocompromised state, termed immunesenescence. One of the most striking features of immune ageing is the progressive shrinkage (involution) of the thymus that is characterised by the loss of thymic epithelial cells (TECs), expansion of perivascular spaces, increased thymic adiposity and the accumulation of senescent cells; together resulting in a loss of functional spaces for the development of thymocytes. Collectively this compromises the process of thymopoiesis and result in a reduced thymic output of naïve T cells and the homeostatic expansion of peripheral memory T cell subsets. Further, chronic lifelong antigenic stimulation leads to the accumulation of senescent T cells in the periphery, which impair tissue immunosurveillance and drive a state of prolonged basal inflammation in aged individuals, termed inflammageing.

Despite these interesting findings, the relationship between intestinal barrier dysfunction and immune ageing is poorly understood. Herein we report that intestinal membrane permeability increases with age in humans and is accompanied by enhanced systemic microbial translocation that contributes to the lifelong antigenic burden, driving a reduction in naïve T cell thymic output and an accumulation of terminally differentiated, senescent T cells in the periphery. The emergence of these hallmarks of T cell ageing hinders the ability of these cells to fight invading pathogens and enhances their ability to produce pro-inflammatory cytokines, which ultimately contribute to the inflammatory state of the aged host. Further, we demonstrate that aged germ-free mice, which do not exhibit age-related intestinal barrier dysfunction, are protected from the accumulation of microbial products in the thymus and maintain their thymic architecture. Together, these findings provide novel evidence of a causal relationship between intestinal barrier dysfunction and T cell ageing.

If measures of biological age are in fact reflections of the burden of damage and dysfunction making up degenerative aging, then we should expect there to be correlations between an accelerated biological age greater than chronological age and risk of conditions such as diabetes that are already known to be associated with increased mortality and reduced life span. The study here shows that to be the case for two aging clocks that are derived from blood chemistry measures rather than omics data.

Cardiometabolic diseases (CMDs) have emerged as the most significant health challenges. Cardiometabolic multimorbidity (CMM) refers to the coexistence of two or more CMDs, including conditions such as stroke, ischemic heart disease (IHD), and type 2 diabetes (T2D). Populations with CMM have a two-fold increased mortality risk and a 12-15 year reduced life expectancy than those with single CMDs. Biological aging, which is associated with decreased metabolic rates, vascular stiffening, chronic inflammation, and oxidative stress, as well as the interplay of comorbidities, may underlie the progression of CMDs to CMM.

The ideal measurement strategy for biological aging should include as many system indicators as possible. For predicting disease, the PhenoAge and Klemera-Doubal method Biological Age (KDM-BA) are the best-validated algorithms according to blood-chemistry-derived measures in multi-ethnic cohorts of older adults. Accelerated aging refers to the phenomenon where an individual's biological age advances more rapidly than their chronological age. This concept goes beyond the mere passage of time, as it emphasizes the underlying biological processes and pathological changes. Thus, this study used both algorithms to test the association between biological aging and CMM.

The study included 415,147 individuals with an average age of 56.5 years. During the average 11-year follow-up period, CMD-free individuals with accelerated aging had a significantly greater risk of CMD (KDM-BA, hazard ratio [HR] 1.456; PhenoAge, HR 1.404), CMM (KDM-BA, HR 1.952; PhenoAge, HR 1.738), dementia (KDM-BA, HR 1.243; PhenoAge, HR 1.212), and mortality (KDM-BA, HR 1.821; PhenoAge, HR 2.047) in fully-adjusted Cox regression models. Accelerated aging had adjusted HRs of 1.489 (KDM-BA) and 1.488 (PhenoAge) for CMM, 1.434 (KDM-BA) and 1.514 (PhenoAge) for dementia, and 1.943 (KDM-BA) and 2.239 (PhenoAge) for mortality in participants with CMD at baseline.

Link: https://doi.org/10.3389/fpubh.2024.1423016

Here find an interesting review of the sex differences observed in the development of atherosclerosis in humans. This condition, in which fatty plaques develop to narrow arteries, is the leading cause of mortality in our species. Plaques rupture to cause blockage of a downstream vessel and a heart attack or stroke. The authors here focus on differences between the sexes in cellular senescence and inflammation in the vasculature. Men tend to bear a greater burden of both of these mechanisms. The implication is that senolytic and anti-inflammatory therapies will benefit men more than women in the specific context of atherosclerotic cardiovascular disease.

The prevalence of coronary artery disease (CAD) is higher in men than in women, but the underlying molecular basis for this sexual dimorphism are poorly understood. There is a consensus on the protective role of estrogens and CAD risk increasing following menopause. Likewise, men develop lipid-rich plaques, whereas women are more likely to develop fibrous plaques with a unique transcriptomic and proteomic signatures in the plaque. Otherwise, presentation of oxidative stress and inflammation may differ between women and men but are inconsistent.

In healthy humans, aging is associated with a progressive endothelium-dependent dilatory decline, which appears 10 years earlier in men than in women and is highly predictive of future cardiovascular events. In recent years, research has established that age-related accumulation of senescent cells could cause chronic low-grade cold inflammation, also known as inflammaging, through the release of the senescence-associated secretory phenotype (SASP). Because SASP involves a range of proinflammatory factors with important paracrine and autocrine effects on cell and tissue biology, inflammaging could promote cardiovascular disease (CVD).

We prospectively collected distal segments of lesion-free internal thoracic arteries during coronary artery bypass graft surgeries from both men and women. Our data show that endothelial dysfunction is more pronounced in men compared to women. Importantly, using single-nuclei transcriptomics, senescent and inflammatory transcriptomic signatures suggestive of the inflammaging were only identified in male endothelial cells, not in female endothelial cells. Therefore, senescence-associated endothelial dysfunction may contribute to atherogenesis in men.

Link: https://doi.org/10.1016/j.jacbts.2024.06.012

The composition of the gut microbiome, the species present and their relative proportions, varies between individuals. Further, the balance of populations shifts with age in ways that are harmful to health. A growing body of animal and human data suggests that the composition of the gut microbiome is just as influential on long-term health as lifestyle choices such as level of physical activity. Some inroads have been made into identifying distinct features of the gut microbiome that are characteristic of specific age-related conditions, or of long-lived individuals.

As is the case for gene variants, even very small effects on mortality risk will lead to sizable enrichment of a specific gut microbiome characteristic in long-lived people. Thus we might expect that most of what is discovered via this sort of research will be of little practical use as a basis for interventions to slow aging and extend healthy life span. Nonetheless, it is interesting to watch the research community move from identifying specific microbial species that are present in greater numbers in long-lived individuals to trying to figure out exactly what those microbes are doing to increase the odds of living longer.

Biosynthetic potential of the gut microbiome in longevous populations

The gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1,029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species.

Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts.

We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of triterpenes and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.

Brain age is a measure of volume and structure of the brain derived from machine learning techniques applied to databases of imaging of brain tissue at various ages and in healthier individuals versus patients with neurodegenerative conditions. Here, researchers demonstrate that, as one might expect, brain age is higher in patients with mild cognitive impairment and Alzheimer's disease. Surprisingly, however, there is a greater acceleration of brain aging in the earlier mild cognitive impairment stage than in the later Alzheimer's disease stage. This is another data point indicating the need for early intervention in the path towards Alzheimer's disease.

Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI). We included control participants (healthy controls or HC), individuals with mild cognitive impairment (MCI), and individuals with Alzheimer's disease (AD). We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model.

We predicted brain age with a mean absolute error (MAE) of less than 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term.

Link: https://doi.org/10.3389/fnagi.2024.1433426

Since its discovery, there has been some interest in the longevity-associated variant of human BPIFB4. It appears to reduce inflammation and improve function in the aging heart, reducing the incidence and impact of heart disease. Of particular interest is that it improves capillary density in heart tissue; recall that capillary density declines with age. Researchers are now working towards gene therapies and protein therapies that deliver the variant BPIFB4 as a way to treat forms of cardiomyopathy in the aged heart. Interestingly it appears that this protein can be delivered orally, which is quite unusual, and no doubt one of the reasons why there is greater interest in this approach versus others.

Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits.

Proteins are effective biotherapeutics and have several advantages over gene therapy, especially for prolonged treatments. In the present study, we investigated the possibility that the LAV-BPIFB4 protein protects cardiac health in older and obese mice with type 2 diabetes. Results show that LAV-BPIFB4 therapy can benefit both conditions, indicating that this longevity-associated protein can antagonize two prevalent risk factors for heart failure. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females.

Link: https://doi.org/10.1186/s12933-024-02487-6