The interaction between the gut microbiota and the innate and adaptive immune systems through direct engagements at mucosal surfaces or microbiota derived metabolites is unambiguous. The peripheral immune system is quite sensitive to slight alterations in the circulating metabolites and plasma cytokine composition, which can result due to microbiota dysbiosis. Intriguingly, parabiosis or plasma transfer experiments that expose a young animal to old blood decreases hippocampal neurogenesis, promotes microgliosis and, ultimately, impairs learning and memory function. On the other hand, exposing aged animals to young blood improves the cerebral vasculature, enhances neurogenesis in the subventricular zone and ameliorates the decline in olfaction.

The brain has long been thought to be immune-privileged. However, the test of time has proved this terminology not absolute. Under homeostatic conditions, the degree of immune-privilege varies depending on age and neurological health. Additionally to the aforementioned age-associated alteration of the microbiota in aging, the neurovascular unit of the blood-brain barrier undergoes a transition which could potentially allow atypical primary or secondary microbiota-derived molecules uptake into the central nervous system (CNS). Indeed, beyond peripheral immunity, microbiota-derived signaling molecules have been implicated in CNS immunity, neuropsychiatric, and neurodegenerative disorders

Compared to other understudied CNS innate immune cells, the microbiota-microglia axis has been well investigated during development and adulthood. There is an evident gap in understanding the direct and indirect links between the microbiota and CNS innate immune cells other than microglia. This gap is even wider when it comes to investigating these interactions in the context of aging. It is difficult to comprehend the biological and molecular basis of senescence, as well as the interplay between microglial senescence and the gut microbiota regulating various functions in the healthy and diseased brain. This, however, represents a therapeutic opportunity that could lead to the discovery of new pharmacological targets for maintaining or restoring physiological tasks in long-lived individuals.

Although the exact mechanisms of cognitive decline are not yet known, it is understood that progressive breakdown of the intricate communication between neurons and glial cells, reduced efficacy of action potential conduction and processes such as neuroinflammation lead to a non-autonomous and gradual loss of cognitive function. White matter tracts functionally connect various areas of the central nervous system (CNS), and are predominantly populated by myelinated axons.

This has led to a growing field of interest and understanding of brain aging as a network deterioration, such that the loss of myelination in white matter tracts which connect cortical regions underlies the loss of cognitive functions which rely on this network connectivity and efficient neuronal transmission. Non-human primate work has found direct links between reduced myelination index, of specific corticocortical and corticobasal tracts and cognitive performance in normal aging.

Myelin is a lipid-rich membrane structure, which wraps concentrically around axons. In the CNS, myelin is provided by terminally differentiated cells of the oligodendrocyte lineage, which hereafter will be referred to as mature oligodendrocytes. Developmental myelination of the CNS takes place largely within the first 2 years of life, but white matter volume increases up until around mid-life as new axonal projections become myelinated. Adult myelination is highly plastic, modifiable by experience, and seems to have important roles in learning and memory and normal cognitive function. Oligodendrocytes are derived from specific neural progenitor cells; oligodendrocyte progenitor cells (OPCs). OPCs populate the CNS, and proliferate throughout life to self-renew, and differentiate to provide a continuous source of new mature oligodendrocytes.

It is widely accepted that there is an overall loss in white matter volume with age in non-pathologically aging human brains. Considering the widespread and specialised roles of myelin, it follows that myelin degradation leads to cognitive decline during 'normal' aging, that is in the absence of clinical age-related pathology such as dementia. This is not least as a result of leaving axons exposed and vulnerable to damage, as is well documented in demyelinating conditions such as multiple sclerosis. Longitudinal data shows that age-related myelin degeneration largely contributes to loss of cognitive function through disconnection of cortical regions, due to slowed processing speeds, which in fact appears to be independent of axonal degeneration. White matter loss and degeneration may result in age-related cognitive decline via several independent mechanisms.

The chronology of neuronal loss and myelin damage is not yet understood. Therefore, it could be hypothesised that a good understanding of the health of oligodendrocytes in the aging brain and how white matter might be protected in aging is ever more important as a potential prophylactic approach to age-associated disease.

The exhaustion and senescence of T cells are two dominant dysfunctional states in chronic infections and cancers. The principle features of exhausted T cells is the elevated inhibitory receptors, including PD-1, Tim-3, and LAG-3 with impaired cytotoxicity and effector cytokine production. Senescent T cells have a distinct phenotypes that include downregulated expression of the costimulatory molecules CD27 and CD28, and high expression of CD57, KLRG-1, and CD45RA. They share common features with senescent somatic cells such as DNA damage, declines in proliferation and activation, but are able to produce high amounts of proinflammatory cytokines. The dysfunction of exhausted T cells can be reversed by immune checkpoint blockades whereas senescent seems to be irreversible. The exhausted and senescent T cells share overlapping characteristics but they are two distinct dysfunctional states.

The accumulation of senescent T cells was first found in the peripheral blood of elderly people. Therefore, T cell senescence is thought to be attributed to the failing efficacy of vaccination and the increased morbidity and mortality from infections and cancer in ageing. Soon thereafter, an increase in senescent T cells was also detected in young patients with chronic viral infections or autoimmune disorders. This phenomenon indicates that in addition to ageing, repeated antigenic stimulation and a chronic inflammatory environment can also lead to T cell senescence. Considering that T cells may be constitutively activated by antigens and influenced by numerous inflammatory cytokines, the tumour microenvironment may be the origin of senescent T cells.

Increasing evidence suggests a link between T cell senescence and tumour progression. Studies have indicated that the tumour microenvironment promotes the senescence of T cells through multiple pathways. The accumulation of senescent T cells may be responsible for advanced cancer and the low response rate to chemotherapy and radiotherapy, as well as immunotherapy. Thus, preventing and restoring T cell senescence could be novel therapeutic strategies for cancer treatment.

Late-life depression, compared to depression at a young age, is more likely to have poor prognosis and high risk of progression to dementia. A recent systemic review and meta-analysis of the present antidepressants for late-life depression showed that the treatment response rate was 48% and the remission rate was only 33.7%, thus implying the need to improve the treatment with other approaches in the future.

Recently, agents modulating the glutamatergic system have been tested for mental disorders such as schizophrenia, dementia, and depressive disorder. Ketamine, a noncompetitive NMDA receptor (NMDAR) antagonist, requires more evidence from randomized clinical trials (RCTs) to prove its efficacy and safety in treating late-life depression. The metabotropic receptors (mGluRs) of the glutamatergic system are family G-protein-coupled receptors, and inhibition of the Group II mGluRs subtypes (mGlu2 and mGlu3) was found to be as effective as ketamine in exerting rapid antidepressant activity in some animal studies.

Inflammation has been thought to contribute to depression for a long time. The cytokine levels not only increase with age but also decrease serotonin. Regarding late-life depression, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) released in vivo are likely to contribute to the reduced serotonin level. Brain-derived neurotrophic factor (BDNF), a growth factor and a modulator in the tropomyosin receptor kinase (Trk) family of tyrosine kinase receptors, probably declines quantitatively with age. Recent studies suggest that BDNF/TrkB decrement may contribute to learning deficits and memory impairment.

In the process of aging, physiological changes in combination with geriatric diseases such as vascular diseases result in poorer prognosis of late-life depression in comparison with that of young-age depression. Treatments with present antidepressants have been generally unsatisfactory. Novel treatments such as anti-inflammatory agents or NMDAR agonists/antagonists require more studies in late-life depression. Last but not least, late-life depression and dementia, which share common pathways and interrelate reciprocally, are a great concern. If it is possible to enhance the treatment of late-life depression, dementia can be prevented or delayed.

Scientists had previously reported that removing senescent glia from mouse models of tauopathy protected them from neurodegeneration. But what made those glia senescent to begin with? Researchers now claim it was tau. They detail how tau oligomers inflamed astrocytes in culture, prompting them to expel a protein called high mobility group box 1 (HMGB1). HMGB1 then led adjacent cells down the path to senescence. Inhibiting HMGB1 release prevented this culture of corruption and, in mouse models of tauopathy, it not only reduced senescent astrocytes but also the amount of tau oligomers and tangles. The animals' short-term memory also improved.

HMGB1 is a nuclear protein involved in DNA replication and repair. Its appearance in the cytosol signals cellular senescence. Released by glia, it can activate nearby cells to crank out inflammatory cytokines, ultimately damaging tissue through a process called senescence-associated inflammation. Researchers previously found HMGB1 in the cytosol of astrocytes that were surrounded by tau oligomers in Alzheimer's disease (AD) and frontotemporal dementia (FTD) postmortem tissue. Did HMGB1 relocalization within astrocytes indeed indicate senescence and contribute to tau pathology?

To find out, researchers examined frontal cortex tissue taken postmortem from eight people who had had AD, six people who had FTD, and eight age-matched controls. In the AD and FTD samples, 75 percent of astrocytes were senescent and had oligomers of tau within or nearby. Researchers found HMGB1 in their cytoplasm. Did the oligomers cause senescence? To find out, the researchers cultured astrocytes from healthy wild-type mice and treated them with oligomers made from recombinant human tau. The astrocytes took up the oligomers. Eleven days later, HMGB1 had turned up in the cytoplasm, ultimately escaping into the culture medium. Seventy percent of the tau-exposed astrocytes also expressed p16 and had high β-gal activity.

Would inhibiting HMBG1 release from cells have any benefit in the brain? To find out, researchers treated 12-month-old hTau mice with ethyl pyruvate (EP) and glycyrrhizic acid (GA), two inhibitors of HMGB1 release, three times a week for eight weeks. These mice express six isoforms of human tau and have significant tangles, gliosis, neurodegeneration, and cognitive problems by 1 year of age. Compared to control mice, inhibitor-treated mice were more curious about new objects and environments, hinting that their short-term memory had improved. In keeping with this, the treated mice had fewer tangles and less phosphorylated tau in the hippocampus.

Chronic loss of cardiomyocyte integrity underlies human heart failure (HF) associated with aging that often involves progression of acute myocardial infarction (MI) and the maladaptive response of cardiomyopathy. During MI, the membrane repair function of cardiomyocytes is compromised, and protection of membrane integrity is an important strategy to treat MI and HF. In addition, chronic oxidative stress and inflammation associated with aging can render the cardiomyocytes more susceptible to stress-induced MI. Therefore, a therapeutic approach that restores tissue integrity and mitigates inflammation can potentially be an effective means to treat age-related organ dysfunction.

We previously identified MG53 as an essential component of cell membrane repair. MG53 nucleates the assembly of the membrane repair machinery in a redox-dependent manner. Mice without the MG53 gene develop cardiac pathology due to defective membrane repair and increased susceptibility to cardiac injury. Transgenic mice with sustained elevation of MG53 in the bloodstream (~100 fold higher circulating MG53 vs wild type mice) lived a healthier and longer lifespan compared with the littermate wild type mice, and displayed increased tissue healing and regeneration capacity following injury. While we have demonstrated that intravenous administration of recombinant human MG53 (rhMG53) protein could protect against acute heart injury in rodent and porcine models of ischemia-reperfusion induced MI, whether rhMG53 has beneficial effects on chronic HF remains to be determined.

Here we demonstrate that the expression of MG53 is reduced in failing human heart and aging mouse heart, concomitant with elevated NFκB activation. We evaluate the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements reveal beneficial effects of rhMG53 treatment in improving heart function of aging mice. Biochemical and histological studies demonstrate the cardioprotective effects of rhMG53 are linked to suppression of NFκB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administrations of rhMG53 in aged mice do not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.

Dietary restriction (DR) is believed to be one of the most promising approaches to extend life span of different animal species and to delay deleterious age-related physiological alterations and diseases. Among others, DR was shown to ameliorate acute kidney injury (AKI) and chronic kidney disease (CKD). However, to date, a comprehensive analysis of the mechanisms of the protective effect of DR specifically in kidney pathologies has not been carried out.

The protective properties of DR are mediated by a range of signaling pathways associated with adaptation to reduced nutrient intake. The adaptation is accompanied by a number of metabolic changes, such as autophagy activation, metabolic shifts toward lipid utilization and ketone bodies production, improvement of mitochondria functioning, and decreased oxidative stress. However, some studies indicated that with age, the gain of DR-mediated positive remodeling tends to gradually decrease. This may be an obstacle if we seek to translate the DR approach into a clinic for the treatment of kidney diseases as most patients with AKI and CKD are elderly.

It is well known that aging is accompanied by impairments in a huge variety of organs and systems, such as hormonal regulation, stress sensing, autophagy and proteasomal activity, gene expression, and epigenome profile, increased damage to macromolecules and organelles including mitochondria. All these age-associated changes might be the reasons for the reduced protective potential of the DR during aging. Here we summarize the available mechanisms of DR-mediated nephroprotection and describe ways to improve the effectiveness of this approach for an aged kidney.

Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach.

A total of 4,587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset.

Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77), ischemic heart disease (0.66), angina (0.73), Alzheimer's disease (0.80), hypertension (0.70), type 2 diabetes (0.88), high cholesterol (0.81), and venous thromboembolism (0.92). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36) showed the opposite.

Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at age 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite.

In conclusion, the present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.

The transcription of the eukaryotic nuclear genome is performed by three, evolutionarily conserved, multi-subunit RNA polymerases (Pols) that each transcribe a distinct set of genes. A large proportion of the nuclear genome is transcribed by Pol II to generate both coding and non-coding RNAs. In contrast, Pol I only transcribes a single gene, albeit present in multiple copies within the genome, to produce the precursor to most rRNAs. While Pol I and III transcribe fewer genes, they generate some of the most abundant cellular RNAs accounting for much of the cellular transcriptional activity.

Pol III function has also extended beyond the canonical role in transcription of the nuclear genome to now include responses to DNA viruses and homologous recombination-mediated repair of DNA double-strand breaks. Pol III mediated transcription is involved in a wide range of biological processes including cell and organismal growth, cell cycle, stemness and differentiation, development, regeneration, and cellular responses to stress. As a result, Pol III subunits have been implicated in a wide variety of disease states.

More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. The evolutionary conservation of Pol III affirms its potential as an exciting, novel therapeutic target for ageing and age-related health.

Many factors contribute to chronic inflammation in the elderly. Cellular damage or stress can initiate a release of mitochondrial damage-associated molecular patterns (DAMPs). As part of this process, mitochondrial DNA (mtDNA) can be released into the extracellular space as circulating cell-free mitochondria DNA (ccf-mtDNA). Due to the similarities between mtDNA and bacterial DNA, this release can in turn elicit a sterile inflammatory response through activation of the innate immune system.

Recent attention has focused on detection and characterization of ccf-mtDNA in the blood. In general, higher plasma/serum levels of ccf-mtDNA have been reported in inflammatory-related diseases, and in response to acute tissue injury such as trauma, acute myocardial infarction, or sepsis. The relationship between ccf-mtDNA and aging is more complex as one report showed an initial decline in ccf-mtDNA into middle-age and then a gradual increase after the fifth decade of life. Individuals greater than 90 years of age with high levels of ccf-mtDNA had higher levels of the proinflammatory cytokines.

Little is known about whether mtDNA is present in plasma extracellular vesicles (EVs) under normal physiological conditions or whether mitochondrial components are important functional cargo in EVs. To address this need, we isolated plasma EVs and analyzed mtDNA levels with human age. Individuals in this aging cohort had donated plasma at two different time points approximately 5 years apart, which enabled us to examine both cross-sectional and longitudinal changes. In both our cross-sectional and longitudinal analyses, EV mtDNA levels decreased with advancing age.

Mitochondrial dysfunction contributes to the aging process. A few recent studies have examined whether mitochondrial components may be functional cargo in EVs. These studies point to a potential mechanism whereby mtDNA in EVs can be transferred to recipient cells and elicit functional changes. However, it is not fully understood whether this is a general mechanism or specific to certain cell types or stimuli. Nevertheless, these initial studies highlight the potential importance of mtDNA in EVs. To further address this, we examined whether EVs from young and old individuals with different mtDNA levels affect mitochondrial function. Cells treated with EVs from old individuals, which contain lower mtDNA levels, had significantly lower basal and maximal respiration than cells treated with EVs from young individuals. These data suggest that EVs from old individuals may impair mitochondrial function.

We here review the loss of muscle function and mass (sarcopenia) in the framework of human healthspan and lifespan, and mechanisms involved in aging. The rapidly changing composition of the human population will impact the incidence and the prevalence of aging-induced disorders such as sarcopenia and, henceforth, efforts to narrow the gap between healthspan and lifespan should have top priority.

There are substantial knowledge gaps in our understanding of aging. Heritability is estimated to account for only 25% of lifespan length. However, as we push the expected lifespan at birth toward those that we consider long-lived, the genetics of aging may become increasingly important. Linkage studies of genetic polymorphisms to both the susceptibility and aggressiveness of sarcopenia are still missing. Such information is needed to shed light on the large variability in clinical outcomes between individuals and why some respond to interventions while others do not.

We here make a case for the concept that sarcopenia has a neurogenic origin and that in manifest sarcopenia, nerve and myofibers enter into a vicious cycle that will escalate the disease progression. We point to gaps in knowledge, for example the crosstalk between the motor axon, terminal Schwann cell, and myofiber in the denervation processes that leads to a loss of motor units and muscle weakness. Further, we argue that the operational definition of sarcopenia should be complemented with dynamic metrics that, along with validated biomarkers, may facilitate early preclinical diagnosis of individuals vulnerable to develop advanced sarcopenia.

Do we have any successes with gene therapy specifically in the rejuvenation field?

That's a little further out. I mean, most are in pre-clinical animal trials or in very tiny, not yet approved human trials. But yes, pre-clinical animal trials are looking good. We published two papers, one on three genes that spread from the site to which they were delivered systemically, and another one about three genes that are localized; these are the so-called Yamanaka factors that cause rejuvenation. Those are two different studies.

Therapies for animals is something that one of your many start-ups, Rejuvenate Bio has been doing. Recently, it has secured another 10 million in funding, and it has been alive for a few years, so what is the situation there?

Rejuvenate Bio was involved in both of those papers, and those were both in mice, and they since have taken one of those two combination gene therapies, three different genes, things like fibroblast growth factor (FGF21), the soluble form of the TGFß receptor, and aKlotho. Anyway, that three-gene combination has then been moved into dog trials. So, this is not an animal model, this is an actual veterinary product, because people do care quite a bit about their pets.

Do you think an abundance of private initiative is the way to go when it comes to fighting aging, or maybe governments should play a greater role?

I think, and some of my colleagues agree, that we need to re-educate the FDA to be more interested in preventative medicine and in aging as a disease, and I think that's a fine goal, but that could take time, and that's uncertain. I think it's easier and probably better to just accept that something that works on the core, fundamental components of aging will also reverse several different types of diseases simultaneously. We are working on eight different diseases. In a way, diseases of aging are even better than biomarkers, because they are really what we care about. That doesn't require the FDA to think revolutionary new thoughts or wrap their heads around something strange. It also has advantages over preventative medicine. I love preventative medicine, we work on it, but to convince a cautious federal agency to give a dose of something powerful to someone who is already healthy...

So, most preventative medicine has been very benign, a very "do no harm" sort of thing. But in this case, if you work on eight different diseases of aging, and some of them have a fairly early onset, and you can actually show reversal, you will get approval. Then you will have, as a side benefit, preventing all the other diseases. You will not only cure the early-onset disease, you will prevent all the others. That is, if you have the right thing.

Do we even know how to aim at life extension?

I don't think we do. I think if we get serious aging reversal, it's something that we can continue to improve on, just like we improved on transportation from the first wheel to rocket ships, or the way we moved from being able to sequence a few base pairs of DNA to being able to sequence the entire biosphere. The thing is to get the foot in the door where we're actually working on the core processes of aging, on the clock that decides that a mouse is going to die in two years and bowhead whales die in two hundred. If we get to that core thing, then we can keep improving it, and, if you keep reversing, there is a chance that you can do that for a very long time. But I don't think this should be the goal. It's hard to do clinical trials on that. The trial where you show that you've extended life by even fifty years would be a very expensive, very long clinical trial. So, let's just focus on things we can do in weeks.

A key feature of age-related immune erosion (termed "immune aging") is the loss of naïve T cells. This loss is often attributed to the involution of the thymus during adulthood however naïve T cells can be maintained for decades by homeostatic proliferation within lymph nodes and secondary lymphoid tissues. Naïve cell loss is instead caused by a breakdown in peripheral homeostasis during the aging process. Naïve T cell homeostasis is multi-faceted, requiring both cell survival and the retention of a quiescent state. Recent studies in humans highlight that naïve cells not only decline numerically in lymph nodes, but they also break quiescence, acquiring a distinct, partially differentiated state during aging.

Stem cell quiescence is a reversible state of growth arrest that plays an important role in tissue homeostasis and regeneration. Recent work in the area of stem cell biology has established that quiescence is not a passive process but is actively maintained by transcriptional and post-transcriptional regulation, including chromatin modification and microRNA-mediated gene repression. Notably, there are distinct levels of stem cell quiescence, ranging from 'deep' to 'shallow' that correlated with more rapid responses and altered functional capacity in both mice and man.

Biologically, naïve T cells are relatively similar to quiescent stem cells, particularly in their high pluripotency and proliferative potential. However, unlike stem cells, the extracellular cues for exit from quiescence are unique to naïve T cells. These cells classically retain a quiescence state until they encounter a specific antigen within their local lymph node niche. Upon direct antigen activation, naïve T cells exit quiescence, rapidly proliferate and can differentiate into numerous functional states depending on numerous factors including the local cytokine and cellular milieu.

In turn, the regulation of activation and the maintenance of cellular quiescence in T cells is extremely important for immune homeostasis, as its failure can lead to significantly perturbed immunity, such as autoimmune disease, cancer, or increased infection. In aging, proliferation capacity of naïve T cells appears intact however pluripotency is diminished; naïve T cells from older individuals display reduced ability to form memory and skewing of subset polarization. These data collectively suggest a partial breakdown in cellular quiescence.

The socioeconomic and health consequences of our ageing population are well documented, with older adults living in long-term care facilities amongst the frailest possessing specific and significant healthcare and social care needs. These needs may be exacerbated through the sedentary behaviour which is prevalent within care home settings. Reducing sedentary time can reduce the risk of many diseases and improve functional health, implying that improvements in health may be gained by simply helping older adults substitute time spent sitting with time spent standing or in light-intensity ambulation.

This study identified the impact of 1 year of lifestyle intervention in a group of older adults living in a long-term care setting in Italy. One hundred and eleven older adults (mean age, 82.37 years) participated in the study. Sixty-nine older adults were in the intervention group (35 without severe cognitive decline and 34 with dementia) and 42 older adults were in the control group. Data on physical functioning, basic activities of daily living (BADL) and mood were collected 4 times, before, during (every four months) and after the 1 year of intervention. The lifestyle intervention focused on improving the amount of time spent every week in active behaviour and physical activity (minimum 150 min of weekly activities).

All participants completed the training program and no adverse events, related to the program, occurred. The intervention group showed steady and significant improvements in physical functioning and a stable situation in BADL and mood following the intervention in older adults with and without dementia, whilst the control group exhibited a significant decline over time. These results suggest that engagement in a physical activity intervention may benefit care home residents with and without dementia both physically and mentally, leading to improved social care and a reduced burden on healthcare services.

Researchers tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health. They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilized to understand biochemical pathways that may be affected by Alzheimer's disease (AD).

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.

Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the "aeRobic Exercise And Cognitive Health (REACH) Pilot Study". The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.

Results showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training. Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho. The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia. Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingolipids, and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.