Fight Aging! Newsletter, September 27th 2021

Vascular dysfunction is entwined with aging and the pathogenesis of Alzheimer's disease (AD), and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of amyloid-ß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia.

To understand whether the ability of HBOT to change CBF and affect cognitive function also applied to elderly people, we performed a human study in which six elderly patients (age 70.00 ± 2.68 years) with significant memory loss at baseline (memory domain score < 100) were treated with HBOT (60 daily HBOT sessions within 3 months). CBF and cognitive function were evaluated before and after HBOT. CBF was measured by MRI, while cognitive functions were evaluated using computerized cognitive tests. Following HBOT, there were significant CBF increases in several brain areas.

At baseline, patients attained a mean global cognitive score (102.4±7.3) similar to the average score in the general population normalized for age and education level (100), while memory scores were significantly lower (86.6 ± 9.2). Cognitive assessment following HBOT revealed a significant increase in the global cognitive score (102.4 ± 7.3 to 109.5 ± 5.8), where memory, attention and information processing speed domain scores were the most ameliorated. Moreover, post-HBOT mean memory scores improved to the mean score (100.9 ± 7.8), normalized per age and education level (100). The improvements in these scores correlate with improved short and working memory, and reduced times of calculation and response, as well as increased capacity to choose and concentrate on a relevant stimulus.

Blood vessels are essential to transport oxygen and nutrients, remove CO2 and other waste products, and, thus, maintain homeostasis in the body. Blood vessels that vascularize the central nervous system (CNS) acquire specific anatomical and functional characteristics that collectively form the blood-brain barrier (BBB). At the cellular level, the BBB is developed by continuous non-fenestrated endothelial cells (ECs) encompassed by pericytes, smooth muscle cells, astrocytes, microglia, oligodendroglia, and neurons that are altogether called the neurovascular unit (NVU). At the molecular level, the BBB ECs are compacted by claudins, occludins, and ZO-1 [tight junction (TJ) proteins] and junction adhesion molecule (JAM) proteins to restrict the paracellular and transcellular diffusion of molecules in the CNS.

In addition, the BBB ECs mediate influx transporters to select metabolite uptake from the blood and efflux transporters to remove toxins and waste products from the brain into the blood. In BBB ECs, leukocyte adhesion molecules (LAMs) express very low to suppress immune surveillance in the brain. Thus, the BBB confines the access of neurotoxic compounds, blood cells, and pathogens to the brain. In addition, the BBB sustains the homeostasis of the brain through tight regulation of the transport of molecules between the brain parenchyma and peripheral circulation.

Hence, the BBB is a fundamental and crucial element of normal and healthy brain function. Any impairment in the cellular or molecular components causes BBB breakdown that results in BBB dysfunction. Aging is one of several factors involved in the breaking of the BBB and was first observed in aged patients reported in the 1970s. In dysfunctional BBBs, the possibility of permeability increases; thus, toxic and blood-borne inflammatory substances that infiltrate the brain could change the biochemical microenvironment of the neurons, thus leading to neurodegenerative diseases and dementia. It has been reported that BBB disruption in aged people is strongly related to Alzheimer's disease (AD) and cognitive impairment.

Although researchers have reported the contributions of BBB disruption to the pathogenesis of cognitive impairment associated with normal aging and dementia, more research is needed to elucidate the precisely causing factors and the cellular and molecular mechanisms of BBB maintenance, breakdown, and repair correlated with neurodegeneration and cognition decline. In the future, how aging and dementia affect BBB function in health and disease state, thus leading to neurodegeneration and cognitive impairment, should be explored in living organisms. Clinical research pertaining to this will boost our knowledge and help us better understand the association between BBB breakdown and cognitive decline. Such studies pave the way for the use of the BBB as a novel biomarker and therapeutic target to treat dementia and other neurological diseases associated with cognitive impairment.

Many studies of the causes of aging and disease have focused on the accumulation of mutations in genes - the blueprints for a cell's proteins and other molecules. Far fewer have looked at glitches in how each blueprint gets translated, which can create faulty proteins. Key to translation is the ribosome, the cellular machinery that uses DNA's instructions to assemble amino acids into proteins. When the ribosome makes a mistake, the resulting proteins may fold improperly, stick to other proteins, and sometimes cause damage to cells.

Researchers looked to a part of the ribosome known to be critical for accurate translation: a protein called RPS23. While analyzing genetic data from species across the tree of life-from cows to gut microbes - the researchers found the same amino acid at a key position in this ribosomal protein. But there was an exception: Certain species of single-celled organisms called archaea that thrive in extremely hot and acidic environments had a mutation that replaced this amino acid with another.

Curious about the effects of this mutation, the researchers used the gene editor CRISPR to swap it into RPS23 genes of yeast, fruit flies, and the tiny roundworm Caenorhabditis elegans. Organisms with the mutation had fewer protein synthesis errors than unmodified controls. All three types of organisms could also survive at higher temperatures. Most strikingly, the yeast cells, flies, and worms lived between 9% and 23% longer. The mutants also seemed healthier as they aged: Compared with the control counterparts, older flies with the mutation were better able to climb and older modified worms produced more offspring.

Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.

For several decades it has been generally accepted that Alzheimer's disease is caused by the accumulation of amyloid proteins in the brain. These proteins form toxic aggregations known as plaques and it is these plaques that damage the brain. Although doubts are growing regarding the veracity of the "amyloid hypothesis," the build up of these plaques is still the most prominent physiological sign of Alzheimer's. And one of the more interesting hypotheses that has been suggested is that these damaging amyloid proteins originate in the liver.

The big challenge in investigating this liver-amyloid hypothesis is that amyloid is also produced in the brain. Most mouse models used in Alzheimer's research involve engineering the animals to overexpress amyloid production in the central nervous system, which only really resembles the minority of humans suffering from hereditary early-onset Alzheimer's. The vast majority of people developing the disease instead experience what is known as sporadic Alzheimer's, where the disease develops in older age, with no familial or genetic history.

The breakthrough in this new research is the development of a new animal model of Alzheimer's disease. Here, the researchers engineered a mouse to produce human amyloid proteins solely in the liver, and this allowed for novel observations into how these proteins can enter the bloodstream and travel to the brain. This new study offers clear evidence of a "blood-to-brain pathway." Using the newly developed mouse model the study shows how amyloid produced in the liver can move to the brain and cause damage leading to pathological signs similar to those seen with Alzheimer's disease.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

There has been tremendous progress in understanding aging and showing that it is possible to reverse it, and there is a growing longevity industry validating the approach to treat aging directly. Researchers are using a variety of approaches, from drugs that get rid of old cells to gene and stem cell therapies. Institutions researching aging include the nonprofit SENS Research Foundation, David Sinclair's lab at Harvard, and biotech companies including Calico (a sister company of Google), Rejuvenate Bio, BioAge, Cambrian, Unity Biotechnology, Juvenescence, Retro Biosciences, and Oisin Biotechnologies.

Both donors and investors see promise in reversing aging. However, there is research that the private sector will not do on its own because investors seek quick returns and donors have only so much money. It has taken seven years to fundraise for clinical trials to see if metformin slows down aging. And there has been more research in mice than in people, partly because clinical trials for people cost more. Basic research is risky, expensive, and without a certain payoff, so important research goes undone because the private sector is unwilling to fund it. The government needs to fill in the gap.

If we discovered a cure for aging, it would make society much wealthier, and the benefits to mankind would be enormous. Increasing life expectancy by one year alone by slowing down aging is worth 38 trillion, according to a recent study-more than the entire national debt of 29 trillion. Finding a cure for aging would significantly boost GDP by allowing people to work for longer. It would also lower the national debt, because higher GDP would lead to more tax revenue, and less would need to be spent on Medicare and Social Security because people would be healthier for longer.

Unfortunately, aging receives only 6% of government health research funding. There has been far more government spending on treating individual diseases, but as Vijay Pande and Kristen Fortney wrote for Andreessen Horowitz, curing cancer would add only four years to the average lifespan "because another major killer like stroke would be just around the corner. Only by targeting aging itself can we make significant impact on improving quality of life and healthspan." It would be more valuable to find a cure for aging than for individual diseases like cancer because it would stop those diseases from materializing in the first place. You're at much greater risk of cancer and Alzheimer's at age 70 than at age 30, and a cure for aging could fundamentally change that. U.S. life expectancy has been roughly stagnant, rising only 7% since 1980. We should target life expectancy as an important measure of national well-being, in addition to GDP. A cure for aging would boost life expectancy far more than finding a cure for individual diseases because aging increases people's risk of disease.

A key mechanism that may contribute to differences in lifespan between species is the maintenance of the proteostasis network. Protein stability or proteostasis refers to the capacity to protect protein structures and functions against environmental stressors, including aging. In fact, dysfunction of the protein quality control mechanisms is a hallmark of aging and there is substantial evidence linking proteostasis and longevity. For instance, improved protein stability is determinant for longevity in exceptionally long-lived mollusks and in the naked mole-rat, the longest-living rodent. In addition, interventions that enhance proteome stability can improve health or increase lifespan in model organisms, such as pharmacological chaperones that have been investigated as potential therapeutic targets to reduce the adverse effects of misfolding of aging-related proteins.

A mammalian-wide study of the genomic underpinnings of lifespan has never been carried out with the combined goals of identifying individual mutations linked to longevity; analyzing the functional properties of their genes and the pathways in which they take part; and studying how the stability of proteins coded by these genes may differentiate long- and short-lived species. Here, we performed the largest phylogeny-based genome-phenotype analysis to date, focusing on the detection of individual mutations and genes that underlie the enormous variation of lifespan in mammals. We report the discovery of more than 2,000 longevity-related genes and show that, overall, they present a trend towards increased protein stability in long-lived organisms. In addition, we successfully show that our findings enhance the interpretation of the results of longevity genome-wide association studies that have been carried out in humans.

We discovered a total of 2,737 single amino acid differences (AA) in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance. These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.

A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging - changes in the body and extend limits of human lifespan. However, the majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene-environment and gene-gene interactions, among other factors.

In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant effects of interactions between SNPs in IGF1R, TGFBR2, and BCL2 on survival to age 85 and older. We validated these findings in the Cardiovascular Health Study sample, using survival to age 85+, and to the 90th percentile, as outcomes.

Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research.

Cells have small compartments known as organelles to perform complex biochemical reactions. These compartments have multiple enzymes that work together to execute important cellular functions. Research have now successfully mimicked these nano spatial compartments to create 'artificial mitochondria'. This was achieved through reprogramming of 'exosomes', which are small vesicles (diameter ~120 nm) that cells use for intercellular signaling. The researchers carried out the experiments using microfluidic droplet reactors, which generated small droplets that were of similar size as typical cells. The researchers first aimed to facilitate controlled fusion of these exosomes within the droplets while preventing unwanted fusions.

These customized exosomes were then preloaded with different reactants and enzymes, which turned them into biomimetic nano factories. The team demonstrated this multienzyme biocatalytic cascade function by encapsulating glucose oxidase (GOx) and horseradish peroxidase (HRP) inside the exosomes. The GOx first converts glucose into gluconic acid and hydrogen peroxide. The HRP in turn uses the hydrogen peroxide generated in the first reaction to oxidize Amplex Red to a fluorescent product, resorufin. Next, the researchers wanted to know exactly how well these mini reactors can be uptaken and internalized by the cells. The cells derived from human breast tissues were fed with fused exosome nanoreactors, and their internalization over the next 48 hours was observed. It was found that cells were able to uptake these customized exosomes primarily through endocytosis, along with multiple other mechanisms.

Armed with this knowledge, the team sought to create functional artificial mitochondria that are capable of producing energy inside the cells. To achieve this, ATP synthase and bo3 oxidase were reconstituted into the earlier exosomes containing GOx and HRP, respectively. These exosomes were in turn fused to create nanoreactors that can produce ATP using glucose and dithiothreitol (DTT). It was found that the fused exosomes were capable of penetrating deep into the core part of a solid spheroid tissue and produce ATP in its hypoxic environment.

Researchers have been looking at epigenetics as a cause of ageing processes for some time. Epigenetics looks at changes in genetic information and chromosomes that do not alter the sequence of the genes themselves, but do affect their activity. One possibility is changes in proteins called histones, which package the DNA in our cells and thus control access to DNA. A research group has now studied the epigenome of mesenchymal stem cells. These stem cells are found in bone marrow and can give rise to different types of cells such as cartilage, bone, and fat cells.

"We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice. We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected."

The researchers then investigated whether the epigenome of stem cells could be rejuvenated. To do this, they treated isolated stem cells from mouse bone marrow with a nutrient solution which contained sodium acetate. The cell converts the acetate into a building block that enzymes can attach to histones to increase access to genes, thereby boosting their activity. The treatment caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells. To clarify whether this change in the epigenome could also be the cause of the increased risk in old age for bone fractures or osteoporosis in humans, the researchers studied human mesenchymal stem cells from patients after hip surgery. The cells from elderly patients who also suffered from osteoporosis showed the same epigenetic changes as previously observed in the mice.

Two new molecules, AP39 and AP123, that generate minute amounts of the gas hydrogen sulfide have been found to prevent skin from ageing after being exposed to ultraviolet light found in sunlight. Researchers exposed adult human skin cells and the skin of mice to ultraviolet radiation (UVA). UVA is the part of natural sunlight which damages unprotected skin and can penetrate through windows, and even through some clothes. It causes skin to age prematurely by turning on skin digesting enzymes called collagenases. These enzymes eat away at the natural collagen, causing the skin to lose elasticity and sag, resulting in wrinkles

In the experiments, the compounds AP39 and AP123 did not protect the skin in the same way traditional sun creams prevent sunburn, but instead penetrated the skin to correct how skin cells' energy production and usage was turned off by UVA exposure. This then prevented the activation of skin-degrading collagenase enzymes and subsequent skin damage.

The compounds AP39 and AP123 specifically target the energy generating machinery inside our cells, the mitochondria, and supply them with minute quantities of alternative fuel, hydrogen sulfide, to use when skin cells are stressed by UVA. The direct result of this was the activation of two protective mechanisms. One is a protein call PGC-1α, which controls mitochondria number inside cells and regulates energy balance. The other is Nrf2, which turns on a set of protective genes that mitigate UVA damage to skin and turn off the production of collagenase, the main enzyme that breaks down collagen in damaged skin tissue and causes skin to look significantly more "aged".

Mitochondria form a complex, interconnected reticulum that is maintained through orchestrated remodeling processes, such as biogenesis, dynamic fission and fusion, and targeted degradation of damaged/dysfunctional mitochondria, called mitophagy. These remodeling processes are collectively known as mitochondrial quality control and are initiated by various cues to maintain energetic homeostasis, which is particularly important for tissues with high-energy demands (e.g., skeletal muscle and heart). While the reticulum appears to respond to energetic demand uniformly, mitochondrial quality control acts with remarkable subcellular precision. For example, in both skeletal muscle and heart, impaired or damaged regions of mitochondria are separated from the functional reticulum in response to certain cellular signals, setting the stage for their degradation by mitophagy. However, what governs the spatial specificity of this process is poorly understood.

The cellular energy sensor AMPK senses cellular energy status by monitoring AMP and/or ADP levels. AMP and/or ADP bind to the γ subunit of AMPK, resulting in a conformational change. Muscle-specific knockout of both α subunit isoforms impairs exercises capacity and mitochondrial oxidative capacity, clearly linking energy sensing of AMPK to mitochondrial function as well as tissue function. Indeed, AMPK activation promotes mitochondrial fission in vitro through its direct substrate mitochondrial fission factor (Mff). We and others have previously demonstrated that induction of mitophagy in response to energetic stress (e.g., exercise, fasting, etc.) is controlled by AMPK-dependent mechanisms.

To reconcile the subcellular specificity of mitochondrial quality control with the fact that exercise and other energetic stresses increase ADP and AMP, the known activators of AMPK, we hypothesized that a proportion and/or subtype of AMPK is localized at mitochondria. This pool of AMPK may serve as a gauge of energetic cues, particularly when and where ATP production through oxidative phosphorylation becomes limited. Herein, we uncovered that a particular combination of subunits of AMPK are localized to mitochondria in a variety of tissues, including skeletal muscle and heart in both mice and humans, which we term mitoAMPK.

We show that mitoAMPK is localized to the outer mitochondrial membrane and is activated in response to various stimuli of mitochondrial energetic stress. mitoAMPK activity and activation are spatially variable across the mitochondrial reticulum. Finally, we present evidence that suggests activation of mitoAMPK in skeletal muscle is required for mitophagy in vivo. Discovery of a pool of AMPK on mitochondria and its importance for mitochondrial quality control highlights the complexity of energetic monitoring in vivo and could facilitate development of strategies of targeting mitochondrial energetics to treat diseases related to impaired mitochondrial function.

In those who eventually develop Alzheimer's dementia, amyloid silently builds up in the brain for up to two decades before the first signs of confusion and forgetfulness appear. Amyloid PET scans already are used widely in Alzheimer's research, and now an algorithm developed by researchers represents a new way of analyzing such scans to approximate when symptoms will arise. Using a person's age and data from a single amyloid PET scan, the algorithm yields an estimate of how far a person has progressed toward dementia - and how much time is left before cognitive impairment sets in.

Researchers analyzed amyloid PET scans from 236 people participating in Alzheimer's research studies. The participants were an average of 67 years old at the beginning of the study. All participants underwent at least two brain scans an average of 4½ years apart. The researchers applied a widely used metric known as the standard uptake value ratio (SUVR) to the scans to estimate the amount of amyloid in each participant's brain at each time point. The researchers also accessed over 1,300 clinical assessments on 180 of the participants. The assessments typically were performed every one to three years. Most participants were cognitively normal at the start of data collection, so the repeated assessments allowed the researchers to pinpoint when each participant's cognitive skills began to slip.

Researchers spent years trying to figure out how to use the data in amyloid PET scans to estimate the age at which symptoms would appear. The breakthrough came when they realized that amyloid accumulation has a tipping point and that each individual hits that tipping point at a different age. After this tipping point, amyloid accumulation follows a reliable trajectory. "You may hit the tipping point when you're 50; it may happen when you're 80; it may never happen. But once you pass the tipping point, you're going to accumulate high levels of amyloid that are likely to cause dementia. If we know how much amyloid someone has right now, we can calculate how long ago they hit the tipping point and estimate how much longer it will be until they are likely to develop symptoms."

Researchers have conducted a comprehensive analysis of the metabolites that make up human saliva using samples given voluntarily from a group of 27-to-33-year-old individuals and a group of 72-to-80-year-old individuals. The sample collection was easy and noninvasive. Twenty-seven volunteers supplied their saliva, which they collected themselves at home. These were transferred to the laboratory for analysis. In general, the concentration of metabolites in saliva is very low compared to that in blood and urine, making it more challenging to detect them. However, using a comprehensive method, the researchers identified 99 metabolites, some of which were previously unreported in saliva. They also found that saliva contains information that reflects biological aging. Twenty metabolites, including those related to antioxidative activity, energy synthesis, and muscle maintenance, were lower in the elderly individuals than the young people, whereas one metabolite actually increased.

"It's interesting that ATP, the metabolite related to energy production, increased 1.96-fold in the elderly. This is possibly due to reduced ATP consumption in the elderly individuals. Amongst the metabolites that declined in quantity were two that are related to taste, suggesting that the elderly lose some ability to taste, and others that are related to muscle activity such as swallowing. These age-linked salivary metabolites together illuminate a metabolic network that reflects a decline of oral function during human aging."

Although this is the first comprehensive analysis to be performed on the metabolites of saliva, the researchers are planning to continue this work. In the future, they hope that saliva will be a sample that can be given readily and easily but could provide an enormous amount of information about an individual's health. "In saliva, age-linked metabolites are related to relatively broad metabolic conditions so that age-related information obtained from salivary metabolites may be distinct from that of blood and urine."

Bifidobacterium species are pioneer colonizers of the gut and have been associated with various health-promoting effects, although the precise modes of action remain largely unknown. The abundances of various Bifidobacterium species in the gut vary widely among individuals according to dietary habits, age, and physiological status. One exception is Bifidobacterium longum (B. longum subsp. longum), which belongs to the human core microbiome. This species accounts for a higher proportion of Bifidobacterium species in the gut regardless of host age, is distributed broadly across the human lifespan, and is among a small subset of gut commensals that can colonize the gut for years.

Using a conceptual framework based on evolution and the pathogen transmission theory, we showed that B. longum had formed at least three geographically related populations and established the active transmission of B. longum strains across different types of hosts and according to geography and proximity. Interestingly, we identified a strong and statistically significant association between host age and genetic variations in B. longum genomes.

Our data also provide a molecular basis for host-microbe coevolution, and this knowledge could feasibly be used to promote host health. The causal link between the gut microbiota and host aging has been investigated extensively, and microbiome-based therapies such as dietary interventions, probiotics, and fecal microbiota transplantation have been shown to efficiently alleviate host aging. Some bacteria have been associated with a long human lifespan by analyzing the gut microbiota of centenarians. No chronological threshold or age is associated with an abrupt change in the microbiota composition; rather, these changes proceed gradually over time.

We identified a strong negative association of the genus Bifidobacterium with host age, consistent with previous observations of reduced bifidobacterial counts in the elderly compared with the gut microbiota of two or three other age groups. We further investigated the bifidobacterial species-level composition and identified B. longum as the most dominant of the core bifidobacterial species in the studied cohort. We further determined that the relative abundance of B. longum was also significantly correlated with host age. Interestingly, efforts to associate the genotype of this aging-related species with host age revealed a robustly significant association with the bacterial arginine biosynthesis pathway.

Previous studies have demonstrated many molecular mechanisms by which microbiota may favorably affect host health and aging, based on principles designed to seek possible solutions to those changes experienced during the aging process, including (1) decreased immune system functioning (i.e., immunosenescence) and low-grade chronic inflammation (i.e., inflammaging); (2) inappropriate oxidative stress; (3) impaired gut barrier function; (4) decreased energy supply for colon epithelial cells; and (5) perturbed gut metabolism (e.g., lipid metabolism, glucose homeostasis, vitamin B and conjugated linoleic acid production). Here, we propose another potent mechanistic route that key players (B. longum) in the gut microbiota are capable of generating age-related genomic adaptations in the arginine metabolism pathway, enhancing the bacterial arginine-enriching ability, further modifying arginine flux and the overall metabolome in the gut microbiota, and ultimately achieving protection against host aging.

Increased basal low-grade inflammation is observed with advancing age, which is augmented by physical inactivity. However, data regarding the influence of lifelong exercise training and particularly high-intensity interval training (HIIT) on inflammatory mediators in older men are scarce. Therefore, we examined effects of 6 weeks of aerobic preconditioning followed by 6 weeks of HIIT on inflammatory mediators - interleukin (IL)-6, homocysteine, and high-sensitivity C-reactive protein (hsCRP) - in previously sedentary older men (SED) and masters athletes (LEX). Further, we investigated whether SED exhibited greater basal inflammatory biomarkers compared to LEX.

Twenty-two men (aged 62 ± 2 years) participated in the SED group, while 17 age-matched LEX men (aged 60 ± 5 years) also participated as a positive comparison group. In SED, preconditioning and HIIT caused a reduction in IL-6 compared to enrollment. SED homocysteine did not change throughout, while the decrease in hsCRP after preconditioning and after HIIT compared to enrollment was small. HIIT did not influence IL-6 or hsCRP in LEX. Homocysteine increased from enrollment to post-HIIT in LEX, but all other perturbations were trivial. IL-6 and hsCRP were greater in SED than LEX throughout the investigation, but homocysteine was not different.

Results of this study suggest moderate-intensity aerobic exercise and HIIT lowers IL-6 (and possible hsCRP) in previously sedentary older men. Moreover, lifelong exercise is associated with reduced concentrations of some inflammatory biomarkers in older males, and therefore, physical inactivity, rather than age per se, is implicated in chronic low-grade inflammation. Moreover, physical inactivity-induced inflammation may be partly salvaged by short-term exercise training.