Prostate cancer is an age-related disease. Every man would be diagnosed with prostate cancer, except that most men do not live long enough, dying from other age-related diseases. The frequency of prostate cancer detected by autopsy is 30-fold higher than mortality from prostate cancer so that "more men die with prostate cancer than because of it". The older the man, the higher frequency of autopsy-detected prostate cancer. The frequency of high-grade prostate cancer doubles every ten years.

Atherosclerosis is driven by hyperfunction of numerous cell types, acting locally and distantly. Thus, activation of endothelial cells, smooth muscle cells (SMC), and macrophages contributes to the formation of atherosclerotic plaque. Atherosclerosis originates in childhood and progresses throughout life. It occurs in everyone. It is a hallmark of aging and a "normal disease". Clinical manifestations of atherosclerosis, cardiovascular diseases, are the main causes of death in humans.

Some age-related diseases are so program-like that they are considered to be the norm. Menopause happens in every woman, and therefore it is not commonly viewed as a disease. But atherosclerosis and prostate enlargement (and all age-related diseases) also happen in everyone. One may argue that menopause is not as deadly as cancer. However, it is deadlier than osteoarthritis and Alzheimer's disease. Menopause promotes cardiovascular diseases (CVD), osteoporosis, obesity, type II diabetes, and other diseases.

It is difficult to define a disease, especially an age-related disease. For example, osteoporosis and obesity were not officially recognized as diseases until 1994 and 2013, retrospectively. Whether we define age-related alterations as a disease depends on political, cultural, financial, medical, and social reasons. The main objection to considering age-related diseases such as menopause and presbyopia as diseases is that they happen to everyone. However, disease does not need to be rare to be a disease. For example, everyone may be sick with influenza during their lifetime, but it does not make it any less a disease. Furthermore, no definition of disease includes the requirement that it should not affect everyone.

According to conventional views, aging is a risk factor for developing disease. It is believed that aging can be healthy (without diseases) and that humans can die either from aging or from diseases. It was claimed, "aging should be strongly considered not to be a disease and as such should not be treated." According to hyperfunction theory, aging is not a risk factor, aging is the sum of all age-related diseases. In analogy, the zoo consists of animals and does not exist without animals, but the zoo is not an animal. There is no aging without these diseases. So-called "healthy" aging is slow aging observed in centenarians, who develop diseases later in life. But no centenarian dies from old age, all die from age-related diseases.

To date, a handful of senolytics have been examined in a variety of preclinical models. In naturally aged mice and atherosclerosis mouse models, the dasatinib and quercetin ("D + Q") administration improved cardiac function. In radiation-damaged mice, "D + Q" enhanced exercise capacity. In osteoporosis mouse models, administration of "D + Q" increased bone mass and strength, providing a novel treatment strategy for not only osteoporosis but multiple age-related comorbidities. Adipose tissue inflammation and dysfunction are causative for obesity-related diabetes and insulin resistance, but "D + Q" alleviated metabolic and adipose tissue dysfunction in obese mice, suggesting the potential of senolytics in treating obesity-related metabolic dysfunction and complications.

Senolytic agents have exhibited substantial efficacy in delaying, preventing or alleviating physical frailty, multiple cancers, and a variety of cardiovascular, liver, kidney, musculoskeletal, lung, eye, hematological, metabolic, and neuropsychiatric pathologies as well as complications of cancer treatment and organ transplantation. Through targeting fundamental aging mechanisms, which are considered as "root cause" contributors to multiple chronic disorders, senolytics hold the potential to alleviate over 40 or even more age-related conditions as illustrated by preclinical studies, thus opening a new avenue for treatment of age-related dysfunction and chronic pathologies.

So far, mounting lines of evidence support the efficacy of senescence-targeting agents, namely senotherapeutics, which mainly comprise senomorphics and senolytics. Early preclinical data about senolytics, small molecule agents that eradicate senescent cells, have shown promising indications of effectiveness across several aging and disease models. The first wave of in-human trials with the senolytic combination of "D + Q" suggested decreased senescent cell burden in adipose tissue of patients with diabetic kidney disease and improved physical function in patients with idiopathic pulmonary fibrosis (IPF). Clinical trials with other senolytics, including the flavonoid fisetin and Bcl-xL inhibitors, are currently in progress.

The first clinical trial of senolytics demonstrated an improved physical function in IPF patients after "D + Q" administration in a first-in-human, open-label, and pilot study, warranting evaluation of "D + Q" in expanded randomized controlled trials for senescence-related disorders. Similarly, another pilot clinical trial reported that treatment with "D + Q" reduces senescent cell burden in adipose tissues of patients developing diabetic kidney disease. Specifically, adipose tissue activated macrophages and adipose tissue fibrosis were decreased, as were levels of circulating SASP factors, including IL-1α, IL-6, and matrix metalloproteinases (MMPs), confirming target engagement (senescent cell decreases) using a "hit-and-run" treatment strategy with senolytics.

More recently, an open-label early phase 1 trial of "D + Q" for Alzheimer's disease (SToMP-AD) reported that intermittent senolytic administration decreases tau protein accumulation and neuro-inflammation, preserves neuronal and synaptic density, partly restores cerebral blood flow and reduces ventricular enlargement. The results support the initiation of a randomized, double-blind and placebo-controlled multicenter phase II trial, which aims to further explore the safety, feasibility, and efficacy of senolytics in treating Alzheimer's disease.

A group of adaptive hypotheses claims that aging evolved to control epidemics of infectious diseases. Indeed, pathogens are a universal and powerful selective factor, and the intrinsic disease-independent mortality (lifespan setpoint) of the host is an important parameter in epidemiological models. If the probability of an individual becoming infected is equivalent across the lifespan and no recovery is presumed, older individuals are expected to be infected more often than younger ones. So, the removal of older individuals by aging obviously results in a decrease in chronic pathogen load. If one assumes that infection adversely affects reproduction, shortening the lifespan might paradoxically result in an increase in the population growth rate.

Disease-mediated selection of a shorter lifespan was also suggested as a hybrid model involving elements of population density control, acceleration of evolution, and disease prevention with the emphasis on overcrowding as a reason for epidemic. However, neither model is a universal explanation of aging. Both involve group selection, a condition believed to be rare in nature. Both require constant severe epidemics to sustain the selective pressure against the longer lifespan, a premise that contradicts observations. Furthermore, such epidemics should promote a fast selection of host resistance.

Using realistic epidemiological and population dynamics models, we constructed a theoretical framework, supporting the idea that pathogens may be the force behind the evolutionary benefit of aging. The new model proposes that aging can be a unifying adaptation to limit the establishment and progression of infectious diseases. First, we found that populations of short-lived individuals, in addition to reduced pathogen prevalence, bestow additional benefits when facing epidemics. Novel pathogens infecting a new host species from another species or the environment might require substantial time to adapt to a new host. Our model shows that the shorter lifespan of a species might limit the time window available for such chronic pathogens to evolve better transmissibility, thus preventing zoonotic transmissions.

Next, we found that dramatic declines in infected population densities - bottlenecks - during natural oscillations or migration into a new environment might be associated with pathogen clearance. If the last infected founders die before the density is reconstituted to levels permissive for epidemics, the pathogen will become extinct in that population. This effect depends directly on the species' lifespan. Thus, a short lifespan has population-level benefits. A simulation designed based on this hypothesis demonstrated the scenario of short lifespan selection.

Regarding the pathogen properties, the model assumes chronic pathogens with strong negative effects on reproductive fitness. Such pathogens are present in nature: evolutionary parasitology predicts pathogens to rather sterilize their hosts than shorten their lifespan to facilitate transmission. We found that pathogens with too high or too low infectivity cannot mediate selection of shorter lifespan: if a pathogen is transmitted at a very high level, it infects short-lived and long-lived populations both at high levels, producing no selectivity. If transmission is too low, the prevalence of the pathogen and, therefore, its adverse effects on long-lived strain population growth is insufficient. Selection favoring short lifespans requires a highly (90%) sterilizing pathogen or a combination of mildly (10-40%) sterilizing diseases that can provide a strong cumulative penalty in coinfected hosts.

We modeled a population of short-lived individuals invaded by a long-lived mutant. With this model, we observed the stabilizing selection of shorter lifespans that occurred by the following mechanism: (i) in the early stages, the pathogens and long-lived mutants are spatially separated from each other, allowing mutants to expand due to their low mortality, (ii) the pathogens spread in the area occupied by long-lived hosts and, due to the reasons described above, becomes more prevalent than in short-lived hosts, (iii) higher pathogen prevalence results in higher sterilization and lineage-specific population decline that, in combination with population pressure of short-lived populations, results in a complete displacement of the long-lived individuals.

Unlike previous models of pathogen control type, our scenario does not require group selection or ongoing severe epidemics to explain a limited lifespan setpoint. Importantly, our hypothesis also mitigates the problems associated with the evolution of the host's resistance to pathogens: selective pressure towards the shorter lifespan might be provided by zoonotic pathogens, the exposure to these pathogens is limited, and the likelihood for the evolution of resistance is reduced. In another scenario involving several milder pathogens, each of these pathogens confers only a little selective power to drive the evolution of resistance.

Chronic inflammation is a hallmark of ageing, but its consequences for tissue function remain unclear. Here we demonstrated that bone marrow ageing is defined by niche remodelling, increased IL-1β production by dysfunctional stromal cells and activation of inflammatory response programmes in both haematopoietic and niche cells. This chronic, low-grade inflammation directly contributes to the loss of endosteal mesenchymal populations, impaired osteogenesis and vascular dysfunction. These changes, alongside expanded inflammatory LepR+ MSC cells, drive lineage biases and regenerative defects from the old blood system. Niche inflammation also activates emergency myelopoiesis pathways in hematopoietic cells, reinforcing myeloid cell production at the expense of lymphoid and erythroid commitment. This blunts regenerative responses that rely on acute activation of these pathways, which then cause exacerbated phenotypes following stress in old mice.

A reduction in endosteal niches and expansion of neurovascular central marrow niches that promote megakaryopoiesis through increased production of pro-inflammatory cytokines, including IL-6 and IL-1β, has been previously described. In addition, a role for IL-1β produced by aged macrophages has been implicated in promoting megakaryopoiesis, and for IL-1β produced by myeloid cells in response to the ageing microbiome in promoting myelopoiesis. Here we showed that chronic IL-1β production by endosteal stromal cells acts in trans to induce inflammatory remodelling of marrow LepR+ MSC cells and contributes to many aspects of altered blood production with age, in particular chronic engagement of emergency myelopoiesis. Conversely, blocking IL-1 signalling attenuates central marrow LepR+ MSC niche inflammation and dampens hematopoietic stem cell activation, recovering some differentiation biases and improving acute regenerative potential. We also found that blocking TNFα, another candidate mediator of these effects, did not prevent niche or blood ageing, which highlights the central role of IL-1.

Our findings add to the growing body of evidence for microenvironmental inflammation in driving blood ageing and the specific importance of IL-1β as a driver of this process. They establish IL-1 as a central factor that damages the crosstalk between the bone marrow niche and the blood system, with inflammatory remodelling of the central marrow probably having deleterious consequences for innervation and vascular function. Consistently, IL-1β levels correlated with age-related mortality in human studies. They indicate a potential application of IL-1 inhibitors to improve blood production in the elderly, especially in regenerative settings following chemotherapy or immunosuppression.

Autophagy and its dysfunction are associated with a variety of human pathologies, including aging, neurodegenerative disease, heart disease, cancer, and metabolic diseases, such as diabetes. A plenty of drugs and natural products have been found to modulate autophagy function through multiple signaling pathways. Small molecules or nanomedicine that can regulate autophagy seem to have great potential to intervene in neurodegenerative diseases that are largely due to the accumulation of misfolded proteins.

In general, microglia participate in autophagy by phagocytosis in the central nervous system (CNS). Because of the critical role of autophagy in protein and organelle quality control, the impairment of autophagy will result in accumulation of aggregated proteins and damaged organelles, which are common pathological hallmarks in AD and PD. Accumulating evidence indicates that the autophagy machinery in microglia can contribute to the emergence, acceleration, or amelioration of CNS disease conditions. So far, two specific mechanisms appear to be relevant to CNS pathology: activation of the inflammasome and increase of autophagy protein-mediated endocytosis/phagocytosis. Autophagy pathways are implicated in the regulation of inflammasome function at various steps by removing triggering agents, inflammasome constituents, or downstream effector molecules. As the major cellular component of the innate immune system in the brain, microglia have been found to execute pivotal functions during CNS homeostasis and pathology.

Microglial autophagy and inflammatory response are necessary for protecting against external stimuli. When the inflammatory response in the brain is continuously activated, overactivated inflammasomes can cause neuronal damage. As early as 2006, it was reported that neuronal autophagy dysfunction induces neurodegenerative diseases in mice, and recent studies have linked microglial autophagy to NLR family pyrin domain 3 (NLRP3) inflammasomes, elucidating the important role of NLRP3 inflammasomes activation triggered by autophagy deficiency in microglial cells in the development of Parkinson's disease (PD).

NLRP3, a widely studied oligomeric multiprotein inflammasome complex, is highly expressed in microglia. Microglial hyperactivation of the NLRP3 inflammasome has been well-documented in various neurodegenerative diseases, including PD. Autophagy protects the nervous system by clearing NLRP3 inflammasome activation. Likewise, inflammasome signaling pathways can also regulate microglia activation necessary to balance between required host defense inflammatory response and to prevent excessive and detrimental inflammation.

The emergence of senescent cells in aging people isn't necessarily a problem in and of itself. The problem seems to be that they hang around for too long. Researchers suspect this happens because the immune system in aging individuals isn't up to the task of eliminating them all. And when senescent cells stay put, the cocktail of molecules they produce, and the ongoing immune response, can damage surrounding tissues. Senescence can also contribute to cancer, but the relationship is multifaceted. Senescence itself is a great defense against cancer - cells that don't divide don't form tumors. On the other hand, the molecules senescent cells emit can create an inflamed, cancer-promoting environment

Researchers went hunting for senolytic drugs that would kill senescent cells while leaving their healthy neighbors untouched. They reasoned that since senescent cells appear to be resistant to a process called apoptosis, or programmed cell death, medicines that unblock that process might have senolytic properties. Some cancer drugs do this, and the researchers included several of these in a screen of 46 compounds they tested on senescent cells grown in lab dishes. The study turned up two major winners: One was the cancer drug dasatinib, an inhibitor of several natural enzymes that appears to make it possible for the senescent cells to self-destruct. The other was quercetin, a natural antioxidant that's responsible for the bitter flavor of apple peels and that also inhibits several cellular enzymes. Each drug worked best on senescent cells from different tissues, the scientists found, so they decided to use them both, in a combo called D+Q, in studies with mice.

Scientists have since discovered several other medications with senolytic effects, though D+Q remains a favorite pairing. Further studies from several research groups reported that senolytics appear to protect mice against a variety of conditions of aging, including the metabolic dysfunction associated with obesity, vascular problems associated with atherosclerosis, and bone loss akin to osteoporosis. Despite the excitement, senolytic research remains in preliminary stages. A lot of basic and clinical research must happen first, but if everything goes right, senolytics might someday be part of a personalized medicine plan: The right drugs, at the right time, could help keep aging bodies healthy and nimble. It may be a long shot, but to many researchers, the possibility of nixing walkers and wheelchairs for many patients makes it one worth taking.

To date, numerous studies have reported that taller individuals are healthier and live longer. Nevertheless, the association between adult stature and longevity involves conflicting findings. This study investigated whether taller Polish adults live longer than their shorter counterparts. Data on declared height were available from 848,860 individuals who died in the years 2004-2008 in Poland. To allow for the cohort effect, the Z-values were generated. Separately for both sexes, Pearson's r coefficients of correlation were calculated. Subsequently, one way ANOVA was performed.

The correlation between adult height and longevity was negative and statistically significant in both men and women. After eliminating the effects of secular trends in height, the correlation was very weak (r = -0.0044 in men and r = -0.0038 in women) but significant (p = 0.023 and p = 0.022, respectively). On balance, these findings do not bear out the hypothesis that taller individuals have a longevity advantage. Since taller stature had a predictable effect on lifespan in the oldest old (85+), these results strongly suggest that longevity favours smaller people.

We discuss these findings in an attempt to identify the biological mechanisms that might be responsible for greater longevity in smaller people. We also analyze selected anthropological factors that pertain to height and longevity.

The disruption of mitochondrial function is usually caused by the excessive production of reactive oxygen species (ROS), the uncoupling of the mitochondrial electron transport chain (mtETC), or the expression of aberrant or mutated proteins encoded by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). In addition, mtDNA is more susceptible to mutations due to its proximity to the site of ROS generation and the absence of histone protection. These perturbations are implicated in primary mitochondrial diseases, which are characterized by mutations that affect the nDNA or mtDNA, as well as various age-related diseases, metabolic disorders, heart pathologies, and cancer, which are referred to as secondary mitochondrial diseases.

Mitochondrial homeostasis and proteostasis are essential for the maintenance of mitochondrial function. To this end, mitochondria have renewal mechanisms, such as mitophagy or mitochondrial unfolded protein response (mtUPR), in addition to mitochondrial biogenesis that promotes the growth and formation of new mitochondria. Moreover, other renewal mechanisms have recently emerged, such as mitochondrial-derived vesicles (MDVs). The ability of mitochondria to release their contents into vesicles is a conserved process shared with their bacterial ancestors. When mitochondrial stressors are present, mitochondrial inner and outer membranes become oxidized, leading to their loading into vesicles which are transported to lysosomes or peroxisomes for degradation, removing damaged proteins and thus preventing mitochondrial dysfunction.

All these processes form part of the protein quality control system of the mitochondrion that is vital for mitochondrial function and cell homeostasis. In this review, we focus specifically on mitochondrial biogenesis and the mtUPR and, in particular, on the implication of mtUPR modulation as a potential treatment of primary and secondary mitochondrial diseases. In addition, we discuss the negative consequences of its activation in cancer patients and its overaction in pathological situations.

The manipulation of the gut microbiota composition through dietary changes and intermittent fasting (IF) has emerged as a potentially effective "pharmaco-nutritional" strategy for reversing dysbiosis and host metabolic disorders. However, the conventional medical care system does not yet have the capability of evaluating both the qualitative and quantitative changes that occur in the gut microbiota. At the population level, one potential strategy for the prevention and management of metabolic syndrome should involve the development of a set of approaches related to changes in the microbiota of the gut. TRF stands for time-restricted feeding in animals and time-restricted eating (TRE) in humans throughout a counted number of hours. It allows for a daily fasting duration that is greater than 12 hours, and it does so without affecting either the quality or quantity of the nutrients consumed. Through the involvement of circadian genes and the gut microbiome, time-restricted feeding/eating (TRF/E) provides protection against nutritional challenges that can lead to obesity and metabolic risks. It has been hypothesized that TRF/E may regulate and modulate gut microbiota in order to prevent metabolic disease through multiple pathways.

It is still too soon to determine how TRF/E affects the composition of the gut and the functions it performs through daily feeding and fasting rhythms. Previously, TRF imposed significant alteration in the microbial composition of human gut microbiota. There were substantial alterations and relative richness of bacterial communities in healthy persons using combined effect size measures from linear discriminant analysis (LDA). These communities were classified as either TRF or non-TRF. At the level of the genus, 34 bacteria were enriched in the TRF group, and 18 bacteria were enriched in the non-TRF group. The most numerous genera in the TRF group were Bacteroidetes and Prevotellaceae (prevotella 9 and prevotella 2), while the most numerous genera in the non-TRF group were Escherichia, Shigella, and Peptostreptococcus. Similarly, a study revealed that timed-feeding protocols (TRF, alternate day fasting and caloric restriction) induced measurable shifts in the bacterial compositions in mice that coincide with improvements in metabolism. TRF, on the other hand, was successful in reestablishing cyclical variation in several bacterial families that are thought to play a role in metabolism.

Glia are non-neuronal cells of the brain and nervous system. There are several subtypes of glial cells, including astrocytes, oligodendrocytes, and microglia. A new study involved in vitro experiments using a lipopolysaccharide (LPS) to induce inflammation in cultured glial cells. Lipopolysaccharides are components of Gram-negative bacteria cell walls that can cause an acute inflammatory response by triggering the release of pro-inflammatory cytokines in various cell types, potentially leading to cell death.

The researchers set out to see whether pre-treatment with klotho could protect glial cells against the surge in levels of pro-inflammatory mediators after the administration of LPS. The results showed for the first time in cultured neural cells that klotho can indeed have anti-inflammatory and neuroprotective effects. Klotho not only acts on the metabolic coupling between neurons and astrocytes but is also an important player in modulating glia neuroinflammation. 

In the most simplistic terms, sepsis is a severe host-pathogen interaction. However, sepsis definitions (and research investigations) are largely focused on the host response to the pathogen, as opposed to the pathogen itself. Within this framework, the pathogen is often seen as a static, homogeneous infectious insult that triggers the dysregulated host response. Accordingly, exaggerated sepsis severity outcomes in the aging population have been attributed to either an age-associated waning of immune function (i.e., immunosenescence), or an alteration in baseline inflammatory response (i.e., inflammaging). However, therapeutics targeting the host immune response or inflammatory cascade have consistently failed to improve clinical outcomes of septic patients, in any age group. Conversely, therapeutic strategies targeting the pathogen with antimicrobial agents have consistently demonstrated significant decreases in sepsis-associated morbidity and mortality.

Given the importance of the pathogen to sepsis outcomes, we sought to determine if longevity-associated changes in gut microbial virulence contribute to aging-associated sepsis severity. We hypothesized that throughout the lifetime of the host, the gut microbiota accumulate virulence factors that promote host immune evasion. Escape of these age-conditioned pathogens from the intestinal lumen therefore leads to exaggerated sepsis severity. This novel concept - that the gut microbiota also "ages" throughout the lifespan of the host and selects for hypervirulent pathobionts - has the potential to inform targeted therapeutic approaches to mitigate the burden of sepsis in older adults.

We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Our findings highlight a previously unrecognized contributor to the pathophysiology of heightened aging-associated sepsis severity. To date, investigations of the intersection of aging and critical illness have focused on longevity-associated host processes such as waning immune function and alterations in inflammation. However, it is intuitive that the intestinal microbiota simultaneously undergoes genomic and phenotypic changes throughout the lifespan of the host organism. This aging of an enteric bacterial community likely selects for pathobionts with virulence factors that offer a fitness benefit - such as the evasion of host immunity. Our work highlights that pathogen virulence factor genomics, and not simply type of pathogen, is therefore a major mediator of mechanistic sepsis heterogeneity.

Zebrafish spontaneously regenerate their retina in response to damage through the action of Müller glia. Even though Müller glia (MG) are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration with precise temporal roles for macrophages and microglia.

Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging, but are still metabolically active, releasing pro-inflammatory signaling molecules as part of the Senescence Associated Secretory Phenotype (SASP). Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after damage.

Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.

Autophagy, such as a double-edged sword, can maintain cell survival and delay aging, but excessive autophagy can lead to cell death and promote aging. Therefore, how to precisely regulate and activate autophagy while clarifying the interaction between autophagy and epigenetic modifications may contribute to anti-aging methods. Epigenetic modification, unlike DNA mutations, is a reversible regulation. CR prevents aging and aging-related diseases, in part through autophagy and reversing abnormal aging-related epigenetic alterations. This suggests that epigenetic modification is expected to be a potential therapeutic strategy against aging and its aging-related diseases. Further understanding of the role of epigenetics in human aging and longevity requires a deeper understanding of the influence of the external environment on epigenetics, such as the mechanism of epigenetics in CR-mediated longevity regulation.

Observational studies have shown that CR also has beneficial effects on human longevity. Among many well-known anti-aging strategies, CR has been identified as one of the effective interventions to combat the aging process and age-related pathological diseases (e.g., diabetes, kidney disease, cardiovascular disease, cancer, Alzheimer's disease, etc.). Thus, CR may influence the aging process by favorably affecting human health, and it is of considerable importance to be used to identify the underlying signaling mechanisms of aging. Mechanisms that extend lifespan through CR modulation of autophagic function or epigenetic modifications have also gradually been explored and focused. In this paper, we focus on autophagy and epigenetics to explore the molecular mechanism of caloric restriction delaying aging and its interactive relationship, providing a basis for the study of aging.

Previous research suggested infection with HSV increases a person's risk of developing Alzheimer's disease (AD). Likewise, someone who caught Epstein-Barr virus (EBV), which causes mononucleosis, is a whopping 32-fold more likely to develop multiple sclerosis (MS). Now, researchers have analyzed medical records from 344,000 people from the Finnish nationwide biobank, FinnGen, and 106,000 in the U.K. Biobank. All participants were of European ancestry and older than 60 at baseline. About 405,500 were healthy, while 44,500 had been diagnosed with an NDD: 11,650 with AD, 2,750 with vascular dementia, 18,700 with all-cause dementia, 7,200 with Parkinson's disease, 840 with amyotrophic lateral sclerosis, and 3,500 with multiple sclerosis.

Researchers compared NDD diagnosis to prior hospitalization with 32 common viral illnesses, including flu, pneumonia, viral warts, chickenpox/shingles, viral encephalitis, and meningitis. Viral exposure was based on hospital billing, so the researchers could not say whether it was the infection or something else that sent a person to the hospital. Any one of 12 of the illnesses correlated with a higher incidence of any of the six NDDs in both databanks. Notably, most of these viral illnesses are caused by neurotropic viruses - those that are able to get into the central nervous system (CNS) and into neurons. These include influenza viruses, HSV, the herpes zoster virus that causes chickenpox/shingles, various enteroviruses that cause meningitis, and EBV.

Which viral illness posed the greatest NDD risk? People who had had viral encephalitis were 31 times more likely to develop AD and 40 times likelier to have dementia of any kind than were people not hospitalized for infection. Likewise, AD risk jumped a whopping 62-fold after meningitis. And it was not just infections of the brain. People hospitalized for a viral intestinal infection had three to five times the risk of developing AD or vascular dementia. Viral hepatitis tripled PD risk, while herpes zoster boosted the likelihood of developing vascular dementia and MS two- to sixfold.

Since infections are typically acute and neurodegenerative disease can advance slowly over years or decades, researchers wondered if the risk for NDDs wanes after infection. They found that it was highest the first year, then fell over 15 years. For example, hazard ratios for all-cause dementia slid from 83 within a year of viral encephalitis to 24 over the next four years, then to five by year 15. What does this all mean for middle-aged folks? Researchers noted that all these cases were in people who had severe symptoms and, therefore, didn't represent someone who rode out the flu or shingles at home. Preventing severe viral illness by getting vaccinated against the flu, pneumonia, or shingles may partially protect someone from getting an NDD. Indeed, a previous analysis concluded that people who got flu or pneumonia shots were less likely to get AD than the unvaccinated.

Among people who received more intensive treatment for high blood pressure, evaluations of MRI scans indicated a positive change in brain structures involved in its ability to clear toxins and other byproducts. The study is the first to examine whether intensive blood pressure treatment may slow, or reverse structural changes related to the volume of the brain's perivascular spaces, areas of the brain around the blood vessels that are involved in the clearance of toxins and other byproducts. These areas tend to enlarge as people get older or have more cardiovascular risk factors.

"If the brain cannot properly clear toxins and metabolic byproducts, they will accumulate and may contribute to the development of dementia. Some research has proposed that the pulsations of the cerebral arteries with each heartbeat help to drive the clearance of these toxic brain byproducts in the perivascular spaces. However, high blood pressure over the long term stiffens arteries, impairing function and the ability to clear toxins, resulting in enlargement of perivascular spaces."

The researchers analyzed brain MRI scans for 658 participants (average age of 67 years, 60% women) of the SPRINT-MIND MRI substudy. After an average 3.9-year follow-up period, 243 people in the intensive treatment group (systolic blood pressure goal of 120 mm Hg) and 199 people in the standard treatment arm (systolic blood pressure goal of 140 mm Hg) had pre- and post-MRI scans that were analyzed for the percentage of brain tissue taken up by perivascular spaces.

In MRI scans taken when the study began, the percentage of brain tissue occupied by perivascular spaces was higher among the patients who were older and had a greater volume of white matter hyperintensities. After controlling for age and sex of the participants, at the start of the study, the volume of perivascular spaces was similar among participants in both blood pressure treatment groups. After almost 4 years of high blood pressure treatment, the volume of perivascular spaces had decreased significantly in the intensive treatment group but did not change in the standard treatment group.