Our mouse longevity study completed with interesting results. Frankly, we did not know what to expect. We tested our products and other promising substances on 245 interbred male C57BL/6 mice. We started the interventions when mice were 300 days old (about 50 in human yrs). Caveats: the sample sizes were very small, optimal dosages were guesses, and we did not weigh the mice - so some effects may be from dietary restriction, etc.

1 C60 99.95 Olive Oil 10%
2 C60 in MCT oil 10%
4 cycloastragenol, NMN, fisetin, icariin, berberine, cistanche, AFA algae
5 exosomes, klotho, FOXO4-DRI, gdf11, epitalon
6 rapamycin, Azithromycin, metformin, NMN, spermidine, echinacea
7 NMN, fisetin, C60
8 RG7834, DHEA, berberine, fisetin, NMN
9 berberine, BHB, NMN, ALA, cycloastragenol, spermidine, DHEA, rhodiola, fisetin, icariin, echinacea, cistanche
10 rapamycin, metformin, aspirin, niacin, RG7834, spermidine, FOXO4-DRI, gdf11
11 centrophenoxine, exosomes, fisetin, metformin
12 double dose fisetin, double NMN, double cycloastragenol
13 klotho, RG7834, spermidine
15 MOTS-C
16 gdf11
17 spermidine
18 double NMN, double berberine, double centrophenoxine, double cycloastragenol, double fisetin
20 NMN, ALA, pterostilbene, cycloastragenol, centrophenoxine, spermidine, DHEA, melatonin, rhodiola, luteolin, fisetin, icariin, echinacea, cistanche, carnitine
21 double fisetin, double NMN, double berberine, NAC, DHEA, echinacea, cistanche

The best intervention was Intervention 1 (red line), C60 Olive Oil (the mouse feed was supplemented with about 10% C60 in organic olive oil). This group also had the largest number of mice (16), so the confidence that something real is happening is greatest with this intervention. The next best group was Intervention 9 (NMN, spermidine, berberine, BHB, ALA, cycloastragenol, dhea, rhodiola, fisetin, icariin, echinacea, cistanche). The following next best interventions are clustered closely around the control, so no conclusions should be made. Surprising that the poorest performer was Intervention #20 (NMN, ALA, pterostilbene, cycloastragenol, centrophenoxine, spermidine, DHEA, melatonin, rhodiola, luteolin, fisetin, icariin, echinacea, cistanche, carnitine) which is similar to the 2nd best performer. Also, Intervention #8 (RG7834, DHEA, berberine, fisetin, NMN) did not do well.

The results with our peptides/proteins did not appear to result in any significant longevity increases. Also, surprising was that the interventions with rapamycin did not appear to produce significant improvements. Lastly, ours is the first lifespan study to investigate C60 with an alternative lipid, we tried MCT oil (basically coconut), and there was no lifespan improvement.

Neurons produce Abeta as an anti-microbial peptide (AMP), a way to protect themselves from microbial assailants. When they come in contact with a pathogen, molecules of Abeta bind to the intruder, which triggers them to stick together into aggregates. Trapping the brain bugs in a sticky web allows Abeta to deactivate the microbial raiders, protecting the brain from infectious assault. With this model, a number of things that scientists have been reporting for years suddenly start to make sense. For one thing, it's long been known that the complement system is activated in the early stages of Alzheimer's disease. The complement system is a part of the innate immune system that directly destroys pathogens by tearing open their membranes, and it was already known to be activated by other AMPs. The model also explains why proteins that are part of the complement system are often found bound up with Abeta plaques in the brain.

If Abeta is an AMP, it also reframes the role of inflammation in the aging and Alzheimer's brain, and the associated activation of brain-resident immune cells called microglia. Microglia are like the macrophages of the brain, gobbling up particulate matter, cellular debris, and other harmful materials in the brain - including, importantly, Abeta - and digesting it in their lysosomes. Microglia have receptors on their surfaces that cause them to spring into action when they get a whiff of activated complement proteins, and Abeta causes dormant complement protein precursors to be converted into their active forms. In the Abeta-as-AMP model, this becomes an elegant host defense system: Abeta is released, traps a marauding microbe in a self-aggregating web of proteins, and then activates complement to help finish off the enemy and to recruit microglia to clean up the battlefield.

This sequence protects the brain from these toxic materials in the short term - first from the infectious intruder, and then from Abeta itself. Abeta is produced in the short term as an emergency response to microbial marauders; microglia are then activated and recruited to clear the dead pathogens and aggregated proteins out of the brain so that they don't cause harm of a different sort. So long as this cycle is executed flawlessly, the brain remains protected from threats and sustains function. But none of these processes are perfect, they leave behind a few microbes here ... a few protein aggregates there ... and a few dysregulated microglia in another corner. Meanwhile, other aging processes make it increasingly difficult to close the loop on the cycle of releasing and aggregating Abeta, destroying pathogens, and recruiting microglia to clean up the battlefield afterward.

Abeta defends the brain against microbial invaders by forming aggregates that capture and neutralize them. Once they've already carried out the attack, the whole snarled-up mess - Abeta polymers, dead microbes, and complement proteins - serves no further purpose and can be toxic to the brain. So Abeta that is cleared out after becoming aggregated has already finished serving a useful purpose, and is mere battlefield rubble that must be safely swept away to help rebuild the neighborhood.

Atherosclerosis is the leading cause of disease, disability, and death in the United States and globally. Current medical practice has made progress, but agonizingly slowly considering the millions of people still adversely afflicted by atherosclerotic complications despite use of current treatments. This review examines how new approaches can significantly reduce the human cost of atherosclerosis. In light of the continued high rate of atherosclerotic disease, what seems needed is what Martin Luther King, Jr. called "the fierce urgency of now". An entire paradigm shift is required such that preventive efforts are embraced much earlier in life, as discussed later in the paper. We propose that preventing and controlling atherosclerosis, the greatest killer of both men and women, be the top priority of medical care in the United States.

While there has been a significant reduction in heart attack and stroke, large numbers of Americans still sustain myocardial and cerebral infarctions and other complications of atherosclerotic cardiovascular disease (ASCVD) Despite the wealth of evidence and the availability of effective preventive interventions, declines in ASCVD hit a nadir, and in fact, cardiovascular mortality has been on the rise over the last decade in both men and women in the US, and throughout the world. Even though modern technology has helped more victims of acute cardiovascular events survive, significant numbers of patients who survive due to stents and other interventions in the immediate acute phase nevertheless often experience long-term disability, reinfarction, and death secondary to inadequate treatment. Further, atherosclerosis causes or contributes to many other diseases besides coronary artery disease. Success cannot be claimed until they are equally addressed and reduced.

Current practices are certainly not eliminating atherosclerotic disease. Atherosclerotic disease is preventable since its drivers of risk are largely modifiable (e.g., hyperlipidemia, hypertension, diabetes, cigarette smoking, sedentary lifestyle, obesity). A more intensive, more precise approach applied earlier than is current practice has a higher likelihood of significantly reducing the total burden of atherosclerotic disease. Atherosclerosis represents a clinical paradox: it is potentially the most preventable or treatable chronic disease, yet it remains the greatest cause of disability and death throughout the world. This does not have to be the case.

There has been compelling and convincing justification for some time that an approach that includes keeping plasma atherogenic lipoproteins low from early in life will greatly reduce risk for ASCVD. The fact that animals, non-human primates, and humans who maintain low cholesterol levels from early in life have very little atherosclerosis all suggest that a 'normal' non-atherogenic LDL-C level is 20-40 mg/dl. That is of course difficult to achieve in a modern society, but may not in fact be necessary. The Tsimane tribe of Bolivia, for example, live unexposed to 'developed' life and are essentially free of atherosclerotic disease. The mean LDL-C and HDL-C in the Tsimane people are at 90 mg/dL and 39.5 mg/dL, respectively.

Alzheimer's disease, a neurodegenerative memory disease, primarily results from the formation of amyloid plaques (Aβ) that gradually inhibit neuron communications. The entire mechanism of Aβ production remains unclear to date, and it is of particular interest among scientists to find out the exact mechanism that produces amyloid precursor protein (APP) cleavage through the amyloidogenic pathway so that effective treatments can be developed.

Our hypothesis states that HSV-1 infection induces APP endocytosis, increases APP cleavage by β-secretase, and raises Aβ levels inside a cell. The Aβ peptides will then exit the cell via exocytosis to form beta-amyloid plaques. Two sets of experiments with the use of human neuroglioma cell lines are proposed to fully investigate the validity of the hypothesis. All of the experiments involve immunoblotting of Aβ using an anti-Aβ antibody, and the results would be analyzed with the assistance of an image analyzer. A significant amount of Aβ would be expected to be present in the cytoplasm of cells with herpes simplex virus (HSV-1) applied, as APP endocytosis would be induced by HSV-1, which produces higher Aβ levels inside the cell.

Overall, we expect a high level of Aβ peptide concentration intracellularly after the introduction of HSV-1 to neuroglioma cell line. However, after the introduction of chloroquine to inhibit endocytosis, the intracellular Aβ concentration would be expected to remain normal even under HSV-1 infection. We also expect a high intracellular but low extracellular Aβ concentration for cell lines introduced with tetanus neurotoxin (TeNT) to inhibit exocytosis as the Aβ peptides are forced to accumulate in the cytoplasm. Lastly, we would expect to observe a high extracellular but low intracellular Aβ concentration for cell lines without TeNT introduction as the Aβ peptides are able to exit cells via exocytosis and aggregate extracellularly.

If all experimental data match the expected results, it can be concluded that herpesvirus infection induces Aβ peptide production in the brain due to an increase in APP endocytosis and that the peptides exit cells via exocytosis to induce the development of Alzheimer's disease.

Some indirect evidence supports the causal relationship between inhibition of growth signaling and longevity if targeted during development. For example, growth hormone (GH) knockout mice and mice lacking GH production live up to 50% longer than their wild-type siblings. However, their longevity was diminished if they were treated with growth hormone during early postnatal development. At the same time, growth hormone knockout induced at adult age had limited to no effects on longevity. However, there have been no experiments where growth pathways are directly inhibited only during development and the longevity outcomes measured.

Rapamycin is a well-characterized mechanistic target of rapamycin (mTOR) inhibitor and is among the most validated and potent pharmaceutical interventions that extend life span in mice. Rapamycin can extend life span if given in adulthood or later in life in various mouse strains, including genetically diverse UMHET3 mice (a cross of four inbred strains). Rapamycin failed to extend the life span of growth hormone receptor knockout mice. Furthermore, early life (EL) rapamycin treatment was previously shown to suppress growth of mice. Thus, rapamycin is a perfect candidate to test how targeting growth only early in life can affect life span, and we used it in our study, examining its effects on longevity, health span, biological age, and gene expression.

Here, we subjected genetically diverse UMHET3 mice to rapamycin for the first 45 days of life. The mice grew slower and remained smaller than controls for their entire lives. Their reproductive age was delayed without affecting offspring numbers. The treatment was sufficient to extend the median life span by 10%, with the strongest effect in males, and helped to preserve health as measured by frailty index scores, gait speed, and glucose tolerance and insulin tolerance tests. Mechanistically, the liver transcriptome and epigenome of treated mice were younger at the completion of treatment. Analogous to mice, rapamycin exposure during development robustly extended the life span of Daphnia magna and reduced its body size. Overall, the results demonstrate that short-term rapamycin treatment during development is a novel longevity intervention that acts by slowing down development and aging, suggesting that aging may be targeted already early in life.

Aging is characterized by the gradual loss of physiological integrity, resulting in impaired function and greater mortality. It is very important to find biomarkers that can prevent aging. In this study, key senescence-related molecules (SRMs) were identified in young and senescent fibroblasts by integrating transcriptome and proteomics from aging tissue/cells, and the correlation between these differentially expressed genes and well-known aging-related pathways. We first combined proteomics and transcriptomics to identify four SRMs. Existing data sets and qPCR confirmed that ETF1, PLBD2, ASAH1, and MOXD1 were identified as SRMs. Then the correlation between SRMs and aging-related pathways was excavated and verified. Next, we verified the expression of SRMs at the tissue level and qPCR, and explored the correlation between them and immune infiltrating cells. Finally, at the single-cell transcriptome level, we verified their expression and explored the possible pathway by which they lead to aging.

Briefly, ETF1 may affect the changes of inflammatory factors such as IL-17, IL-6, and NFKB1 by indirectly regulating the enrichment and differentiation of immune cells. MOXD1 may regulate senescence by affecting the WNT pathway and changing the cell cycle. ASAH1 may affect development and regulate the phenotype of aging by affecting cell cycle-related genes. In conclusion, based on the analysis of proteomics and transcriptome, we identified four SRMs that may affect aging and speculated their possible mechanisms, which provides a new target for preventing aging, especially skin aging.

Despite their obvious promise and growing popularity, epigenetic clocks still have some notable shortcomings. First, it's difficult to tell exactly how accurate biological age measurements are. Epigenetic clocks are much better at predicting lifespan than previous techniques, like oxidative damage or telomere length. But the challenge with longevity research is that studies to determine whether biological age predictions translate to actual lifespans take decades. In other words, if you're 25 with a biological age of 30, will you die five years sooner than average? Secondly, scientists haven't pinpointed which changes are directly caused by aging. It's possible that some changes occur by happenstance in older people, independent of aging. In other words, some changes we associate with aging may not actually impact the length or quality of our lives.

Finally, some scientists suspect that epigenetic clocks are more of a measure of biological age than a driver of it. "Think of the clock as a wristwatch. If you broke your wristwatch, the time would still go on. My guess would be that if we stopped these methylation sites from changing, we wouldn't interfere much with the aging process." But these researchers still see epigenetic clocks as an excellent marker for biological age, a measure of how quickly the aging process is proceeding in humans or other animals, independent of calendar years. For example, a smoker at age 50 might have an epigenetic age of 65, while a person at the same who exercises frequently might have an epigenetic age of 45. Others are a bit more optimistic. "I would say there are DNA methylation sites that actually matter a lot. If you change the right locations, you may actually rejuvenate cells. I won't claim that, I'm just saying nobody knows."

Epigenetic clocks remain a powerful tool in the science of rejuvenation. In the short term, researchers believe their best use is as a measuring tool, a kind of epigenetic yardstick that determines whether other interventions are successful. Although there are outstanding questions about how we define aging, how we measure rejuvenation, and how this could unfold economically, epigenetic clocks are "a true revolution." When it comes to aging research in humans, epigenetic clocks could be a tool that helps quantify a treatment's effectiveness while subjects are still alive. In other words, if epigenetic clocks become sophisticated enough that the FDA accepts them as surrogate endpoints, it would allow researchers to quickly demonstrate a drug's efficacy in mere months by measuring methylation - as opposed to waiting years to see how the drug affects survival. Longevity research could speed ahead, no longer reliant on death as a primary endpoint.

Is there any established correlation between Senescence-Associated Secretory Phenotype (SASP) or senescent cell burden on one side and the measured C-reactive protein level or any other routinely measured inflammatory marker in an individual on the other side? Unfortunately not. Scientists first started asking this question around the time of the first proof-of-concept of the value of destroying senescent cells, and initially hoped it would be a straightforward matter of simply measuring the levels of various SASP factors directly in the blood. While none of the components of the SASP are common blood tests like C-reactive protein, some commercial blood-testing labs do test for specific proteins that are part of the SASP, including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α).

Somewhat surprisingly, however, things did not turn out to be quite that simple, for reasons that aren't entirely clear. Perhaps the SASP factors concentrate too locally around senescent cells to be easily picked up in the blood. Or perhaps it relates to the fact that none of the individual proteins and lipid derivatives released from senescent cells as part of the SASP are actually unique to senescent cells. Instead, all of the proteins that make up the witches' brew of proteins that is the SASP are are repurposed growth factors, protein-degrading enzymes, and above all inflammatory signaling molecules that also produced by non-senescent cells in the body to do things like break down damaged muscle, recruit immune cells, remodel injured tissue, and so on. This might mean that the signal from true SASP factors is swamped out by the fact that those same factors are produced at relatively high levels in an aged person's body for other reasons, in response to their high burden of aging damage.

And precisely because each individual SASP factor is produced by non-senescent cells for other purposes entirely, no one marker can be used as a reliable index of SASP production: the level of any given factor always reflects a mixture of SASP-related production and production for entirely different reasons. As such, measuring just one or even a few SASP factors in the blood and correlating that to the actual number of senescent cells in your body or the level of SASP they're producing is likely a fool's errand from the start.

The mechanical and structural properties of blood vessels differ along the vascular tree. There are two categories of large arteries: elastic and muscular arteries. Elastic arteries are close to the heart, contain more elastin per unit of area and play an important role in buffering the ejected blood volume. More distal muscular arteries have a higher smooth muscle cell content. They regulate wall tension and shear stress by adjusting the vascular tone and transport blood to the smaller resistance vessels that control blood flow.

With increasing age, the structural and cellular components of the arterial wall change. Mechanistically, the arterial wall is largely dependent on the balance between elastin and collagen and their interplay with vascular smooth muscle cell (VSMC) contraction. This balance is disrupted during aging, leading to a higher collagen content, a lower elastin content, more elastin fragmentation, and more cross-linking of both collagen and elastin. On a cellular level, vascular aging is related to endothelial dysfunction and impaired nitric oxide bioavailability, leading to reduced endothelium-dependent vasodilation and therefore more pronounced vasoconstriction. These microstructural and functional changes are typically thought to result in an overall stiffening of the arterial wall.

Researchers have investigated how nitroglycerin (NTG)-mediated vasodilation acutely affects vascular stiffness and whether this differs between elastic and muscular arteries. NTG is an organic nitrate and acts as a nitric oxide (NO) donor. Results show that the arterial stiffness of the carotid artery and the regional carotid-femoral pulse wave velocity (cfPWV) is, as expected, higher in hypertensive individuals than in controls, but this was not observed in the brachial artery. While the stiffness of the elastic carotid artery, as well as cfPWV, increased, the stiffness of the muscular brachial artery did not change significantly. These findings were independent of hypertensive status.

Further analyses revealed that in the carotid artery, the active VSMC stiffness index parameter was lower than the passive ECM stiffness index, whereas these two indices were almost equal in the brachial artery. This results in the hypothesis that the different stiffness responses to vasodilation are a result of the ratio of active to passive stiffness contributions. When this difference is positive (active stiffness is greater than passive stiffness), decreasing arterial tone will decrease the overall wall stiffness as the active contribution decreases. In contrast, when this difference is negative, vasodilation will lead to an increase in stiffness.

In conclusion, this study highlights the importance of investigating whether vasodilatory drugs, used as antihypertensive medication, have an adverse effect on large arteries by increasing their stiffness, which has inherent potential cardiovascular risks.

The older someone is, the more likely they are to get cancer. This was thought to suggest that the human immune system becomes weaker with age and that the same must therefore be true of the killer T cells that play such a critical role in fighting off pathogens. The job of the T cell is to track down and kill virus-infected cells or tumour cells in the body. Up until now the accepted scientific view has been that T cells function less effectively as they age. However, researchers have now found the rather surprising result that the ability of cytotoxic CD8+ T cells to destroy tumour cells does not deteriorate but actually improves with age.

The reason why T cells are such effective killers has to do with the highly effective weapons that they have at their disposal. The production of the molecules perforin and granzyme is enhanced in older T cells. As its name suggests, the molecule perforin perforates the target cells making tiny pores in the cell membrane. Granzyme can then enter the cells and initiate apoptosis, a form of programmed cell death. In addition, older experienced T cells have an accurate picture of who they are supposed to be targeting. Cytotoxic CD8+ T cells have a good memory of who they have attacked and destroyed in the past. And as part of the adaptive immune system, they live and learn. T cells are able to form memory cells. If they come into contact with a pathogen that they are already acquainted with, they respond very quickly and very effectively.

This begs the question as to why older people are not better protected against tumour cells and viruses if their T cells are so powerful. "On the one hand we have age-related processes that occur naturally as the cell ages, but we also have to consider changes in cell function due to the ageing of the cell's environment. In the case of T cells, the evidence seems to suggest that the reason for the deteriorating immune response is not to be found in the T cells themselves but rather in the ageing environment."

Aging results in systemic changes that leave older adults at much higher risk for adverse outcomes following respiratory infections. Much work has been done over the years to characterize and describe the varied changes that occur with aging from the molecular/cellular up to the organismal level. In recent years, the systemic accumulation of senescent cells has emerged as a key mediator of many age-related declines and diseases of aging. Many of these age-related changes can impair the normal function of the respiratory system and its capability to respond appropriately to potential pathogens that are encountered daily.

In this review, we aim to establish the effects of cellular senescence on the disruption of normal lung function with aging and describe how these effects compound to leave an aged respiratory system at great risk when exposed to a pathogen. We will also discuss the role cellular senescence may play in the inability of most vaccines to confer protection against respiratory infections when administered to older adults. We posit that cellular senescence may be the point of convergence of many age-related immunological declines. Enhanced investigation into this area could provide much needed insight to understand the aging immune system and how to effectively ameliorate responses to pathogens that continue to disproportionately harm this vulnerable population.

Women's reproductive cessation is the earliest sign of human aging and is caused by decreasing oocyte quality. Similarly, C. elegans' reproduction declines in mid-adulthood and is caused by oocyte quality decline. Aberrant mitochondrial morphology is a hallmark of age-related dysfunction, but the role of mitochondrial morphology and dynamics in reproductive aging is unclear. We examined the requirements for mitochondrial fusion and fission in oocytes of both wild-type worms and the long-lived, long-reproducing insulin-like receptor mutant daf-2. We find that normal reproduction requires both fusion and fission, but that daf-2 mutants utilize a shift towards fission, but not fusion, to extend their reproductive span and oocyte health.

daf-2 mutant oocytes' mitochondria are punctate (fissioned) and this morphology is primed for mitophagy, as loss of the mitophagy regulator PINK-1 shortens daf-2's reproductive span. daf-2 mutants maintain oocyte mitochondria quality with age at least in part through a shift toward punctate mitochondrial morphology and subsequent mitophagy. Supporting this model, Urolithin A, a metabolite that promotes mitophagy, extends reproductive span in wild-type mothers - even in mid-reproduction - by maintaining youthful oocytes with age. Our data suggest that promotion of mitophagy may be an effective strategy to maintain oocyte health with age.

In this long-term population-based prospective cohort comprising 9,912 participants, we evaluated the risk of mortality according to longitudinal repeated measurements of Frailty Index (FI). Both levels of FI and the proportions of frail participants gradually increased with age and there was significant variability in the progression of frailty. We observed clear dose-response relationships between FI values and all-cause, cancer, and cardiovascular disease (CVD) mortality, with associations being substantially stronger and consistent across various lengths of follow-up when FI was considered as a time-varying predictor variable rather than being based on a single measurement at baseline.

The increase in prevalence of frailty with age is well established in both cross-sectional and longitudinal studies in aging research. For example, in a cross-sectional study among 993 adults aged 70+ conducted in Spain, prevalence of frailty (measured by Fried frailty) was reported to be 7.1%, 14.5%, 29.7%, 31.8%, and 43.2%, in participants aged 70-74, 75-79, 80-84, 85-89 and over 90 years, respectively. In a cohort study conducted in 350 older adults (≥65 years) residing in long-term care facilities in Korea, the prevalence of frailty (measured by Fried frailty) increased from 25.8% to 35.2% during three years of follow-up.The increase in frailty prevalence with age is in line with the expected consequence of the cumulative decline in multiple physiological systems occurring at older age.

Nevertheless, in agreement with results from other recent studies, our study demonstrates that there is substantial inter-individual variability in development and progression of frailty with increasing age, including the possibility of regression of frailty. A variety of factors contributes to the development of frailty and frailty transitions, including nutritional status, environmental factors, diseases, and psychological factors. Therefore, these changeable characteristics make frailty a comprehensive and reversible health condition.

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 85,83 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study.

Here, we find that the gut microbiota explain up to 58% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas. We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition.

There is now increasing evidence that metabolites produced in the gut can enter the brain and impact brain macrophages. The macrophages residing in the brain comprise parenchymal microglia and non-parenchymal macrophages located in the perivascular spaces, meninges, and the choroid plexus. It is important to better understand the underlying mechanisms of age-related dysbiosis, which causes changes in gut-derived metabolites and ultimately influence the central nervous system, as well as immune and endocrine responses of the host.

Several studies have found that microbial metabolites can affect gut-brain responses, affecting the morphology and function of brain macrophages. These changes include their polarization and phagocytic capacity, which, in turn, controls behavior and emotional processes. Levels of microbiota-derived metabolites are elevated in older individuals with age-associated diseases and cognitive defects compared to younger, healthy age groups. The identified metabolites with higher concentration in aged hosts, which include choline and trimethylamine, are known risk factors for age-related diseases.

While the underlying mechanisms and pathways remain elusive for the most part, it has been shown, that these metabolites are able to trigger the innate immunity in the central nervous system by influencing development and activation status of brain-resident macrophages. In this review, we highlight the impact of age on the composition of the microbiome and microbiota-derived metabolites and their influence on age-associated diseases caused by dysfunctional brain-resident macrophages.