Fight Aging! Newsletter, July 24th 2023

In a new paper, researchers demonstrate that gum disease can lead to changes in brain cells called microglial cells, which are responsible for defending the brain from amyloid plaque. This plaque is a type of protein that is associated with cell death, and cognitive decline in people with Alzheimer's. The study provides important insight into how oral bacteria makes its way to the brain, and the role of neuroinflammation in Alzheimer's disease. Using mouse oral bacteria to cause gum disease in lab mice, the scientists were able to track periodontal disease progression in mice and confirm that the bacteria had traveled to the brain. They then isolated the brain microglial cells and exposed them to the oral bacteria. This exposure stimulated the microglial cells, activated neuroinflammation, and changed how microglial cells dealt with amyloid plaques.

Microglial activation is critical for modulating the neuroinflammatory process and the pathological progression of neurodegenerative diseases, such as Alzheimer's disease (AD). Microglia are involved in forming barriers around extracellular neuritic plaques and the phagocytosis of β-amyloid peptide (Aβ). In this study, we tested the hypothesis that periodontal disease (PD) as a source of infection alters inflammatory activation and Aβ phagocytosis by the microglial cells.

Experimental PD was induced using ligatures in C57BL/6 mice for 1, 10, 20, and 30 days to assess the progression of PD. Animals without ligatures were used as controls. Ligature placement caused progressive periodontal disease and bone resorption that was already significant on day 1 post-ligation and continued to increase until day 30. The severity of periodontal disease increased the frequency of activated microglia in the brains on day 30 by 36%. In parallel, heat-inactivated PD-associated total bacteria and Klebsiella variicola increased the expression of TNFα, IL-1β, IL-6, TLR2, and TLR9 in microglial cells in vitro. Incubation of microglia with Klebsiella variicola increased the Aβ-phagocytosis by 394% and the expression of the phagocytic receptor MSR1 by 33-fold compared to the non-activated cells. These results support a direct role of PD-associated pathogens in neuroinflammation.

SRF's ApoptoSENS team are developing ways to target senescent cells that evade existing senolytic strategies while reducing damage to healthy cells. One blind spot in the senolytic story has been the effects of these drugs on "secondary senescent cells." Secondary senescence is a more recently-discovered and understudied form of senescence that occurs when cells are driven into senescence by the signaling molecules released by other cells that had previously become senescent (the "primary" senescent cells). SRF scientists wondered if they might elude many of our existing senolytic drugs, since all such drugs were developed by testing them against primary senescent cells. Sure enough, secondary senescent cells could shrug off several of the best-studied senolytic drugs.

Fortunately, SRF scientists found a novel route of senolytic attack that works well against both types of senescence. These cells intensively engage pathways involved in iron metabolism, and also seem to be primed for ferroptosis, a kind of programmed cell death that depends in part on iron as a trigger. The ApoptoSENS team found that both primary and secondary senescent cells are susceptible to novel attack routes that exploit pain points along this pathway.

Senolytics - senescent cell-destroying drugs - are now one of the most rapidly-advancing rejuvenation biotechnologies. Unfortunately, these drugs do inflict some collateral damage to nonsenescent cells. So how much better might senolytics work if SRF scientists coupled them with strategies to enhance the aging body's flagging regenerative response after treatment? The SenoStem group is preparing to test just such a combination. This team will seek to fortify surviving nonsenescent cells with pro-regenerative signaling factors from mesenchymal stem cells (MSCs).

SRF's MitoSENS team is now working on three ways to deal with mitochondria that bear large deletion mutations. The first approach, which they've been working on since SRF's founding, entails creating "backup copies" of the mitochondrial genes in the nucleus. The team's standout success with the gene ATP8 enabled an engineered backup copy of this gene to express in living mice. Other genes are proving harder to engineer such that their proteins are reliably produced, delivered, and correctly placed in the energy- production machinery. The MitoSENS team is working to overcome the tendency that some mitochondrial proteins have to curl up on themselves.

The MitoSENS team is also in the early stages of working on two alternative strategies. One is a version of a "gene drive," using therapeutic mitochondria engineered with an enzyme that can destroy all the existing mitochondrial genomes in the cell. Once transplanted into an aging patient, these aggressive mitochondria would enter the patient's cells and replicate themselves while buzzsawing through the existing mitochondrial population, replenishing the cell with pristine, functional mitochondria. The other strategy aims to overcome the culling-avoidance superpower of mitochondria that bear large deletions in their genome. The team is testing several different drugs that may be able to force deletion-bearing mitochondria to show their faces and be marked for destruction by the cell maintenance process of mitophagy.

SRF's LysoSENS team is working on an ingenious strategy to clear aging neurons of tau oligomers. Their strategy consists of two major components: a novel cell- penetrating platform to deliver their therapeutic antibody inside the neurons, and the use of catabodies instead of conventional binding antibodies to attack their target. Catabodies, unlike conventional antibodies, cleave their targets into harmless fragments, rather than dragging intact target aggregates one by one out of the brain (and in doing so, damaging the brain's blood vessel barrier). The LysoSENS team is developing both a suite of potential catabodies to test and synthetic tau oligomers against which to test them, to ensure that catabodies that successfully buzz their way through the artificial target will also obliterate the real enemy inside the neuron. When they are satisfied with the oligomers, they will begin testing catabody candidates, and after that move on to studies in cells and in mouse models of tau-driven neurodegenerative aging.

Scientists have been pursuing a way to clear aging cells of lipofuscin for longer than any other LysoSENS target. Past efforts have failed in part because real lipofuscin is hard to isolate from cells, forcing scientists to resort to artificial mixtures of crosslinked materials or a lipofuscin-like material produced by cells under abnormal conditions. With SRF funding, researchers are now attacking the problem using new techniques to isolate true lipofuscin derived from human donor and horse heart tissue. Horse and human heart lipofuscin are very similar, allowing them to work with the larger available quantities of horse material with confidence that the results will also apply to human lipofuscin. The team is now attacking this isolated lipofuscin using the classic LysoSENS strategy of screening environmental bacteria for the ability to survive by breaking it down. Excitingly, their mixed soil bacterial population can degrade lipofuscin and release fluorescent breakdown products. They are now winnowing this population down to determine which species produce the enzymes that do the critical work.

One key change in aging extracellular matrix (ECM) is crosslinking, in which one strand of a structural protein becomes chemically bound to an adjacent strand, limiting both strands' range of motion. Continuous exposure to blood sugar and other essential but highly reactive molecules in the blood can lead to a kind of crosslink termed Advanced Glycation Endproducts (AGE). The evidence currently suggests that the single most common AGE crosslink in the key structural protein collagen is glucosepane. SRF funded research has now shown that each kind of tissue undergoes its own distinct crosslinking pattern, and the crosslinks that form don't simply accumulate over time as was previously believed. Instead, a subset of crosslinks easily breaks during regular tissue stretching, only for new crosslinks of the same type to form afterward.

In fact, while researchers have confirmed that irreversible crosslinks increase in aging tendons with age, this increase is more than counterbalanced by a net loss of the reversible crosslinks, which may contribute to putting us at greater risk of rupturing our tendons as we age. Moreover, while the team has confirmed that the age-related rise in glucosepane seen in human tissues also occurs in mice, there's no sign of some of the other crosslinks previously reported in either species. This careful work is showing that some of these are instead either methodological artifacts or cases of misidentification.

Starting in 1962, researchers demonstrated that nuclei contain the necessary information to generate new individuals with normal lifespans. In 2006, researchers demonstrated that the expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as the Yamanaka factors or OSKM), reprograms the developmental potential of adult cells, enabling them to be converted into various cell types. These findings initiated the field of cell reprogramming, with a string of publications in the 2000s showing that the identity of many different types of adult cells from different species could be erased to become induced pluripotent stem cells, commonly known as "iPSCs".

The ability of the Yamanaka factors to erase cellular identity raised a key question: is it possible to reverse cellular aging in vivo without causing uncontrolled cell growth and tumorigenesis? Initially, it didn't seem so, as mice died within two days of expressing OSKM. But later work confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression or by continuously expressing only OSK, leaving out the oncogene c-MYC. In the optic nerve, for example, expression of a three Yamanaka factor combination safely resets DNA methylomes and gene expression patterns, improving vision in old and glaucomatous mice. Numerous tissues, including brain tissue, kidney, and muscle, have now been reprogrammed without causing cancer. In fact, expression of OSK throughout the entire body of mice extends their lifespan. Together, these results are consistent with the existence of a "back-up copy" of a youthful epigenome, one that can be reset via partial reprogramming to regain tissue function, without erasing cellular identity or causing tumorigenesis.

Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues. This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body. Developing a chemical alternative to mimic OSK's rejuvenating effects could lower costs and shorten timelines in regenerative medicine development. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation.

In this study, we developed and utilized novel screening methods including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells. We identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.

Breakthroughs in medical research in the last century have led to a significant extension of the human lifespan, resulting in a shift towards an elderly population worldwide. Due to the ongoing progress of global development towards elevated standards of living, this study specifically examines Switzerland as a representative nation to explore the socioeconomic and healthcare ramifications associated with an ageing population, thereby highlighting the tangible impact experienced in this context. Life expectancy in Switzerland has steadily increased over the past few decades. Along with life expectancy, the old age dependency ratio (OADR) has also increased. As ageing is associated with many morbidities, their prevalence is destined to further increase unless further measures are taken. The increased OADR will lead to secular stagnation in the economy and threaten the sustainability of pension systems.

The demographic transition and ageing population, therefore, pose important challenges to Swiss society from several perspectives. Given our findings here, we suggest the following potential strategies to address these challenges. A paradigm shift in medical practice is needed to improve health rather than respond to existing diseases. By researching the molecular mechanisms involved in the biology of ageing and expanding epidemiological and clinical research on ageing, we should aim to bridge the gaps between basic research of geroscience and medical applications. We need to establish protocols for clinical trials on ageing that include functional capacity, frailty, and time to events of onset of age-related diseases. For this, we need to establish clinically relevant biomarkers of healthy ageing and incorporate a more complete interconnected picture of comorbidities. With this, we can hopefully improve the quality of health in the ageing population.

Without changes in the biological and medical fields, the socioeconomic impacts of ageing might become devastating. Hence it is indispensable to invest in the future of ageing research.

Fibrosing interstitial lung diseases (f-ILDs) constitute a complex and heterogeneous group of diseases characterized by non-resolving pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most frequent and representative f-ILD. The pathogenesis of f-ILD is complex and still incompletely understood but cell senescence has recently emerged as a potentially relevant pathogenic player. Cell senescence is an adaptation of cells to circumstances of unrepairable cellular damage. The entry in senescence involves a profound rewiring of cellular biology that is largely irreversible, with a permanent exit from the cell cycle (in the case of proliferating cells), the acquisition of stable epigenetic changes, the expansion of the lysosomal compartment and a vigorous Senescence Associated Secretory Phenotype (SASP). The SASP includes multiple pro-inflammatory and tissue remodelling mediators that can foster a fibrogenic cascade and propagate the senescent phenotype to the surrounding cells.

We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib, and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity.

We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.

The long-term maintenance of sensory hair cells faces a fundamental challenge: to maximize sensitivity, hair cells are built to be delicate and fragile, yet they have to withstand continuous mechanical stress. A potent capacity for repair must therefore be considered indispensable, especially for mammalian auditory hair cells that are not regenerated. In our study, we provide evidence for a novel process that repairs lesions in the stereocilia F-actin core. The damaged sites can be visualized as 'gaps' in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments.

Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat containing 2 (XIRP2) is required for the repair process and facilitates the enrichment of monomeric γ-actin at gaps. Recruitment of XIRP2 to stereocilia gaps and stress fiber strain sites in fibroblasts is force-dependent, mediated by a novel mechanosensor domain located in the C-terminus of XIRP2. Our study describes a novel process by which hair cells can recover from sublethal hair bundle damage and which may contribute to recovery from temporary hearing threshold shifts and the prevention of age-related hearing loss.

In atherosclerosis, fat is accumulated in the artery walls creating atherosclerotic plaques. Plaques that rupture can cause a stroke or myocardial infarction, and a deeper understanding of the mechanisms underlying plaque rupture is needed to prevent serious complications. Researchers now show that atherosclerotic plaques in the carotid arteries often rupture at the beginning of the plaque, at a location closest to the heart. "In our study, we were able to pinpoint exactly where plaques rupture. This is an important step, allowing for a better understanding of why they rupture."

The research is based on studies of atherosclerotic plaques in the carotid arteries from a total of 188 individuals. The researchers used electron microscope and RNA sequencing techniques to get a detailed picture of the location where most plaques rupture. High blood pressure and type 2 diabetes are factors that increase the risk of atherosclerosis and therefore these patient groups were also included in the study.

RNA sequencing showed a strong association between the enzyme MMP-9 and the area where plaques rupture. High levels of MMP-9 could also be associated with an increased risk of future cardiovascular disease in individuals with atherosclerosis. The researchers hope to be able to use MMP-9 as a marker to predict which patients are at risk of having a myocardial infarction or a stroke. They are also investigating if it is possible to develop new treatments that reduce the risk of plaque rupture based on inhibition or blockade of MMP-9.

Numerous mechanisms and pathways have been suggested to initiate metabolic syndrome and the eventual development of specific diseases. In particular, there is a wealth of literature connecting metabolic syndrome to increased mitochondrial reactive oxygen species (ROS). The most compelling evidence comes from genetic manipulations in mice. Expression or overexpression of enzymes that determine the superoxide and hydrogen peroxide concentrations in the mitochondrial matrix (superoxide dismutase 2, SOD2; peroxiredoxin 3, PRDX3; mitochondria-targeted catalase, mCAT) are all strongly protective. Further support comes from the use of less specific mitochondria-targeted antioxidants (mitoQ, mitoVitE), and of the peptide SS-31. These lines of evidence strongly implicate mitochondria as the source of superoxide/hydrogen peroxide.

Eleven different sites of superoxide/hydrogen peroxide production associated with the mitochondrial electron transport chain have been identified. Of these, site IQ in complex I, site IIIQo in complex III, and site IIF in complex II have the greatest maximum capacities to generate superoxide/hydrogen peroxide in vitro. Compounds have been identified that specifically suppress superoxide/hydrogen peroxide production from site IQ (Suppressors of Site IQ Electron Leak, S1QELs) and site IIIQo (Suppressors of Site IIIQo Electron Leak, S3QELs) without inhibiting the electron transport chain or affecting oxidative phosphorylation. S1QELs and S3QELs have profound protective effects in cell and organ models, demonstrating the biological importance of superoxide/hydrogen peroxide production from sites IQ and IIIQo.

Existing S1QELs and S3QELs are not well suited for systemic in vivo use because of their poor solubility and bioavailability, although they can be added to the diet to affect gut cell function in flies and mice. WHere, we introduce a novel potent, selective and orally bioavailable S1QEL1: S1QEL1.719. S1QEL1.719 was used to test the metabolic effects of suppressing superoxide/hydrogen peroxide production from site IQ in vivo. C57BL/6J male mice fed a high-fat chow for one, two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome. Daily prophylactic or therapeutic oral treatment of high-fat-fed animals with S1QEL1.719 decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin level.

Although it is widely agreed that proteotoxicity drives impairments in Alzheimer's disease (AD) and other neurological diseases, many preclinical and case-report studies indicate that increased microglial production of pro-inflammatory cytokines such as TNF-a mediate proteotoxicity in AD and other neurological conditions. We developed parallel high-throughput phenotypic screens to discover small molecules which inhibit age-related proteotoxicity in a C. elegans model of AD, and microglia inflammation (LPS-induced TNF-a). In the initial screen of 2,560 compounds, the most protective compounds were, in order, phenylbutyrate (HDAC inhibitor), methicillin (beta lactam antibiotic), and quetiapine (tricyclic antipsychotic). These classes of compounds are already robustly implicated as potentially protective in AD and other neurodegenerative diseases.

In addition to quetiapine, other tricyclic antipsychotic drugs also delayed age-related amyloid-beta (Abeta) proteotoxicity and microglial TNF-a. Based on these results we carried out extensive structure-activity relationship studies, leading to the synthesis of a novel congener of quetiapine, #310, which inhibits a wide range of pro-inflammatory cytokines in mouse and human myeloid cells, and delays impairments in animal models of AD, Huntington's, and stroke. #310 is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction. Among these molecular responses is inhibition of glycolysis, reversing gene expression profiles and elevated glycolysis associated with AD.

Several lines of investigation strongly supported that the protective effects of #310 are mediated by activating the Sigma-1 receptor, whose protective mechanisms in turn also entail inhibiting glycolysis. Reduced glycolysis has also been implicated in the generally protective effects of dietary restriction, rapamycin, reduced IFG-1 activity, and ketones during aging, suggesting that aging is at least in large part a consequence of glycolysis. In particular, the age-related increase in adiposity, and subsequent pancreatic decompensation leading to diabetes, is plausibly a consequence of age-related increase in beta cell glycolysis. Consistent with these observations, the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. To our knowledge no other molecule exhibits all these protective effects which makes #310 a uniquely promising candidate to treat AD and other age-related diseases.

Researchers have discovered a link between the levels of certain bacteria living in the gut and coronary atherosclerotic plaques. The new study was based on analyses of gut bacteria and cardiac imaging among 8,973 participants aged 50 to 64 without previously known heart disease. They were all participants in the Swedish CArdioPulmonary bioImage Study (SCAPIS). "We found that oral bacteria, especially species from the Streptococcus genus, are associated with increased occurrence of atherosclerotic plaques in the small arteries of the heart when present in the gut flora. Species from the Streptococcus genus are common causes of pneumonia and infections of the throat, skin, and heart valves."

The research team also found that some of the species linked to the build-up of atherosclerotic plaques in heart arteries were linked to the levels of the same species in the mouth. Furthermore, these bacteria were associated with inflammation markers in the blood, even after accounting for differences in diet and medication between the participants who carried the bacteria and those who did not. "We have just started to understand how the human host and the bacterial community in the different compartments of the body affect each other. Our study shows worse cardiovascular health in carriers of streptococci in their gut. We now need to investigate if these bacteria are important players in atherosclerosis development."

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells, and brain cell death.

When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons.

Together, this data emphasizes the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

By studying 667 people at various stages of Alzheimer's disease, the researchers discovered in the cerebrospinal fluid that levels of a specific form of tau - known as microtubule binding region (MTBR)-tau243 - track with the amount of damaging tau tangles in the brain and with the degree of cognitive decline. The average age of participants was 71, and the group included healthy people as well as people at all stages of disease, ranging from those with some amyloid in their brains but no cognitive symptoms, to those with extensive amyloid and tau in their brains and a diagnosis of dementia. The researchers compared cognitive function with levels of various forms of tau in the cerebrospinal fluid and with levels of amyloid and tau in the brain, as measured by amyloid and tau PET scans.

The researchers analyzed data from people who volunteered for Alzheimer's research studies through the Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER)-2 program. Levels of MTBR-tau243 in the cerebrospinal fluid correlated strongly with brain tau tangle levels and cognitive function. As MTBR-tau243 levels went up, tau levels in the brain also went up, and scores on cognitive tests went down. In contrast, levels of another form of tau in the cerebrospinal fluid, phosphorylated tau, tracked mainly with brain amyloid levels but not with brain tau levels or cognitive function. By combining the two forms of tau in the cerebrospinal fluid - phosphorylated tau and MTBR-tau243 - the researchers were able to predict cognitive function almost as well as by using tau-PET imaging.

The AMP-activated protein kinase (AMPK) plays a critical role in cellular energy regulation and organismal metabolism. However, previous attempts to genetically manipulate the AMPK complex in mice yielded unfavorable outcomes. In search of an alternative approach, the research team focused on manipulating the upstream nucleotide pool to modulate energy homeostasis.

Using the turquoise killifish as their model organism, the team targeted and mutated APRT, a key enzyme involved in AMP biosynthesis. Remarkably, this manipulation resulted in a significant extension of lifespan in heterozygous male killifish. The study further employed an integrated omics approach, revealing rejuvenation of metabolic functions in the aged mutant fish. These included the adoption of a fasting-like metabolic profile and enhanced resistance to a high-fat diet. At the cellular level, the heterozygous fish exhibited remarkable traits such as enhanced nutrient sensitivity, reduced ATP levels, and activation of AMPK.

The study also unveiled an intriguing observation. The benefits of extended lifespan and rejuvenated metabolic functions were nullified when lifelong intermittent fasting was applied. Furthermore, the longevity phenotypes were sex-specific. The research sheds new light on the potential of targeting APRT as a promising strategy for promoting metabolic health and extending lifespan in vertebrates. Further investigations in this field hold promise for the development of interventions that enhance healthy aging and combat age-related metabolic diseases.

Some individuals, often designated as superagers, can reach late life with the memory function of individuals 30 years younger. Previous neuroimaging studies have shown that superagers have larger hippocampal volumes, thicker anterior cingulate cortices, and slower cortical atrophy than do typical older adults. Previous studies also explored the association between superager status and some lifestyle factors, such as satisfaction with social relationships. However, most studies had small sample sizes and were cross-sectional in nature, hindering distinction between long-standing structural differences and differential atrophy rates in superageing brains compared with normal ageing brains.

One approach to obtaining larger samples of deeply phenotyped (a cohort of participants with a rich set of different variables, including data for clinical history, lifestyle, neuroimaging data, etc) superagers with longitudinal data is to investigate large longitudinal ageing cohorts. We applied this approach to the Vallecas Project longitudinal study aiming, first, to characterise superagers' cerebral grey matter volume, cross-sectionally and longitudinally, relative to that of age-matched typical older adults; and second, to apply machine learning to identify which demographic, lifestyle, and clinical variables are the greatest differentiating factors between superagers and typical older adults.

We included 64 superagers (mean age 81.9 years) and 55 typical older adults (82.4 years). The median number of follow-up visits was 5.0 for superagers and typical older adults. Superagers exhibited higher grey matter volume cross-sectionally in the medial temporal lobe, cholinergic forebrain, and motor thalamus. Longitudinally, superagers also showed slower total grey matter atrophy, particularly within the medial temporal lobe, than did typical older adults. A machine learning classification including 89 demographic, lifestyle, and clinical predictors showed that faster movement speed (despite no group differences in exercise frequency) and better mental health were the most differentiating factors for superagers. Similar concentrations of dementia blood biomarkers in superager and typical older adult groups suggest that group differences reflect inherent superager resistance to typical age-related memory loss.

The circulating levels of soluble Klotho have been observed to decrease with age, which increases the risk of age-related illnesses. Researchers demonstrated accelerated aging and a shortened lifespan in mice when the Klotho gene was silenced or deficient. In contrast, an extended lifespan was seen when the gene was overexpressed. Likewise, in humans, Klotho has been shown to display many beneficial effects, especially related to anti-aging. Although the membrane-bound Klotho protein was first associated with neurodegenerative diseases, it has been linked to various other age-related disease processes, including cancer biology and cardiovascular, renal, and skin diseases.

Klotho plays a role in cancer biology by serving as both a tumor suppressor and prognostic tumor biomarker, thus preventing and detecting neoplasms. Furthermore, Klotho overexpression (KL-OE) reduces the number of cancer cells that survive. Treatment with soluble Klotho has been shown to reduce tumor volume in preclinical cancer models in organs such as the stomach, pancreas, colon, and breast. Concerning the link between cardiovascular illness and Klotho, researchers discovered that decreased cardiac Klotho expression and increased cardiac fibroblast growth factor (FGF) expression lead to higher cardiovascular risk. Klotho can be used as an early and sensitive biomarker for kidney illnesses, as well as a potential treatment for both acute kidney injury and chronic kidney disease (CKD). It is also protective against ultraviolet B (UVB)-induced damage, and its overexpression can considerably alleviate the UVB-induced damage to cells, an effect which can be seen with aging.

Klotho has positive benefits on the neurological system by causing a higher representation of useful longevity genes, preventing further neuronal damage, and offering neuroprotection. Thus, it has the potential to become a new treatment for many age-related diseases that cause dementia, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. In this review, we discuss the mechanisms of Klotho's benefits and roles on various organ systems, specifically on nervous system disorders that lead to dementia.