The Genetics of Aging: A Vertebrate Perspective.

Aging negatively impacts vitality and health. Many genetic pathways that regulate aging were discovered in invertebrates. However, the genetics of aging is more complex in vertebrates because of their specialized systems. This Review discusses advances in the genetic regulation of aging in vertebrates from work in mice, humans, and organisms with exceptional lifespans. We highlight challenges for the future, including sex-dependent differences in lifespan and the interplay between genes and environment. We also discuss how the identification of reliable biomarkers of age and development of new vertebrate models can be leveraged for personalized interventions to counter aging and age-related diseases.

Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states.

Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.

Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING.

Ageing is intimately connected to the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS-STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS-STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing.

An open science study of ageing in companion dogs.

The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan. To take advantage of this opportunity, the Dog Aging Project will collect extensive survey data, environmental information, electronic veterinary medical records, genome-wide sequence information, clinicopathology and molecular phenotypes derived from blood cells, plasma and faecal samples. Here, we describe the specific goals and design of the Dog Aging Project and discuss the potential for this open-data, community science study to greatly enhance understanding of ageing in a genetically variable, socially relevant species living in a complex environment.

An aged immune system drives senescence and ageing of solid organs.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.

Genetic insights into biological mechanisms governing human ovarian ageing.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Better safe than sorry: Naive T-cell dynamics in healthy ageing.

It is well-known that the functioning of the immune system gradually deteriorates with age, and we are increasingly confronted with its consequences as the life expectancy of the human population increases. Changes in the T-cell pool are among the most prominent features of the changing immune system during healthy ageing, and changes in the naive T-cell pool in particular are generally held responsible for its gradual deterioration. These changes in the naive T-cell pool are thought to be due to involution of the thymus. It is commonly believed that the gradual loss of thymic output induces compensatory mechanisms to maintain the number of naive T cells at a relatively constant level, and induces a loss of diversity in the T-cell repertoire. Here we review the studies that support or challenge this widely-held view of immune ageing and discuss the implications for vaccination strategies.

Two conserved epigenetic regulators prevent healthy ageing.

It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated1-6. Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan4,7. Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases8,9 shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.

Slowing of Movements in Healthy Aging as a Rational Economic Response to an Elevated Effort Landscape.

Why do we move slower as we grow older? The reward circuits of the brain, which tend to invigorate movements, decline with aging, raising the possibility that reduced vigor is due to the diminishing value that our brain assigns to movements. However, as we grow older, it also becomes more effortful to make movements. Is age-related slowing principally a consequence of increased effort costs from the muscles, or reduced valuation of reward by the brain? Here, we first quantified the cost of reaching via metabolic energy expenditure in human participants (male and female), and found that older adults consumed more energy than the young at a given speed. Thus, movements are objectively more costly for older adults. Next, we observed that when reward increased, older adults, like the young, responded by initiating their movements earlier. Yet, unlike the young, they were unwilling to increase their movement speed. Was their reluctance to reach quicker for rewards due to the increased effort costs, or because they ascribed less value to the movement? Motivated by a mathematical model, we next made the young experience a component of aging by making their movements more effortful. Now the young responded to reward by reacting faster but chose not to increase their movement speed. This suggests that slower movements in older adults are partly driven by an adaptive response to an elevated effort landscape. Moving slower may be a rational economic response the brain is making to mitigate the elevated effort costs that accompany aging.

From discoveries in ageing research to therapeutics for healthy ageing.

For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.

Chronotropic Incompetence Among People With HIV Improves With Exercise Training in the Exercise for Healthy Aging Study.

BACKGROUND: People with HIV (PWH) have lower exercise capacity than peers without HIV, which may be explained by chronotropic incompetence, the inability to increase heart rate during exercise. METHODS: The Exercise for Healthy Aging Study included adults aged 50 to 75 years with and without HIV. Participants completed 12 weeks of moderate-intensity exercise, before randomization to moderate or high intensity for 12 additional weeks. We compared adjusted heart rate reserve (AHRR; chronotropic incompetence <80%) on cardiopulmonary exercise testing by HIV serostatus and change from baseline to 12 and 24 weeks using mixed effects models. RESULTS: Among 32 PWH and 37 controls (median age, 56 years; 7% female), 28% of PWH vs 11% of controls had chronotropic incompetence at baseline (P = .067). AHRR was lower among PWH (91% vs 101%; difference, 10%; 95% CI, 1.9%-18.9%; P = .02). At week 12, AHRR normalized among PWH (+8%; 95% CI, 4%-11%; P < .001) and was sustained at week 24 (+5%; 95% CI, 1%-9%; P = .008) versus no change among controls (95% CI, -4% to 4%; P = .95; interaction P = .004). After 24 weeks of exercise, 15% of PWH and 10% of controls had chronotropic incompetence (P = .70). CONCLUSIONS: Chronotropic incompetence contributes to reduced exercise capacity among PWH and improves with exercise training.

Modulation of Motor Vigor by Expectation of Reward Probability Trial-by-Trial Is Preserved in Healthy Ageing and Parkinson's Disease Patients.

Motor improvements, such as faster movement times or increased velocity, have been associated with reward magnitude in deterministic contexts. Yet whether individual inferences on reward probability influence motor vigor dynamically remains undetermined. We investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial. We conducted three studies that coupled a reversal learning paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. In Study 1, we tested healthy younger [HYA; 37 (24 females)] and older adults [HOA; 37 (17 females)], and medicated Parkinson's disease (PD) patients [20 (7 females)]. We showed that stronger predictions about the tendency of the action-reward contingency led to faster performance tempo, commensurate with movement time, on a trial-by-trial basis without robustly modulating reaction time (RT). Using Bayesian linear mixed models, we demonstrated a similar invigoration effect on performance tempo in HYA, HOA, and PD, despite HOA and PD being slower than HYA. In Study 2 [HYA, 39 (29 females)], we additionally showed that retrospective subjective inference about credit assignment did not contribute to differences in motor vigor effects. Last, Study 3 [HYA, 33 (27 females)] revealed that explicit beliefs about the reward tendency (confidence ratings) modulated performance tempo trial-by-trial. Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster tempo. We also provide robust evidence for a preserved sensitivity of motor vigor to inferences about the action-reward mapping in aging and medicated PD.SIGNIFICANCE STATEMENT Navigating a world rich in uncertainty relies on updating beliefs about the probability that our actions lead to reward. Here, we investigated how inferring the action-reward contingencies in a volatile environment modulated motor vigor trial-by-trial in healthy younger and older adults, and in Parkinson's disease (PD) patients on medication. We found an association between trial-by-trial predictions about the tendency of the action-reward contingency and performance tempo, with stronger expectations speeding the movement. We additionally provided evidence for a similar sensitivity of performance tempo to the strength of these predictions in all groups. Thus, dynamic beliefs about the changing relationship between actions and their outcome enhanced motor vigor. This positive bias was not compromised by age or Parkinson's disease.

Enhancing healthy aging with small molecules: A mitochondrial perspective.

The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Reduced default mode network effective connectivity in healthy aging is modulated by years of education.

Aging is a major risk factor for neurodegenerative diseases like dementia and Alzheimer's disease. Even in non-pathological aging, decline in cognitive functioning is observed in the majority of the elderly population, necessitating the importance of studying the processes involved in healthy aging in order to identify brain biomarkers that promote the conservation of functioning. The default mode network (DMN) has been of special interest to aging research due to its vulnerability to atrophy and functional decline over the course of aging. Prior work has focused almost exclusively on functional (i.e. undirected) connectivity, yet converging findings are scarce. Therefore, we set out to use spectral dynamic causal modeling to investigate changes in the effective (i.e. directed) connectivity within the DMN and to discover changes in information flow in a sample of cognitively normal adults spanning from 48 to 89 years (n = 63). Age was associated to reduced verbal memory performance. Modeling of effective connectivity revealed a pattern of age-related downregulation of posterior DMN regions driven by inhibitory connections from the hippocampus and middle temporal gyrus. Additionally, there was an observed decline in the hippocampus' susceptibility to network inputs with age, effectively disconnecting itself from other regions. The estimated effective connectivity parameters were robust and able to predict the age in out of sample estimates in a leave-one-out cross-validation. Attained education moderated the effects of aging, largely reversing the observed pattern of inhibitory connectivity. Thus, medial prefrontal cortex, hippocampus and posterior DMN regions formed an excitatory cycle of extrinsic connections related to the interaction of age and education. This suggests a compensatory role of years of education in effective connectivity, stressing a possible target for interventions. Our findings suggest a connection to the concept of cognitive reserve, which attributes a protective effect of educational level on cognitive decline in aging (Stern, 2009).

Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice.

PURPOSE: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. METHODS: Healthy wild-type mice of both sexes (2-21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. RESULTS: Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. CONCLUSION: Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.

Effects of healthy aging and mnemonic strategies on verbal memory performance across the adult lifespan: Mediating role of posterior hippocampus.

In this study, we aimed to understand the contributions of hippocampal anteroposterior subregions (head, body, tail) and subfields (cornu ammonis 1-3 [CA1-3], dentate gyrus [DG], and subiculum [Sub]) and encoding strategies to the age-related verbal memory decline. Healthy participants were administered the California Verbal Learning Test-II to evaluate verbal memory performance and encoding strategies and underwent 4.7 T magnetic resonance imaging brain scan with subsequent hippocampal subregions and subfields manual segmentation. While total hippocampal volume was not associated with verbal memory performance, we found the volumes of the posterior hippocampus (body) and Sub showed significant effects on verbal memory performance. Additionally, the age-related volume decline in hippocampal body volume contributed to lower use of semantic clustering, resulting in lower verbal memory performance. The effect of Sub on verbal memory was statistically independent of encoding strategies. While total CA1-3 and DG volumes did not show direct or indirect effects on verbal memory, exploratory analyses with DG and CA1-3 volumes within the hippocampal body subregion suggested an indirect effect of age-related volumetric reduction on verbal memory performance through semantic clustering. As semantic clustering is sensitive to age-related hippocampal volumetric decline but not to the direct effect of age, further investigation of mechanisms supporting semantic clustering can have implications for early detection of cognitive impairments and decline.

The bottlenose dolphin (Tursiops truncatus): a novel model for studying healthy arterial aging.

Endothelial function declines with aging and independently predicts future cardiovascular disease (CVD) events. Diving also impairs endothelial function in humans. Yet, dolphins, being long-lived mammals adapted to diving, undergo repetitive cycles of tissue hypoxia-reoxygenation and disturbed shear stress without manifesting any apparent detrimental effects, as CVD is essentially nonexistent in these animals. Thus, dolphins may be a unique model of healthy arterial aging and may provide insights into strategies for clinical medicine. Emerging evidence shows that the circulating milieu (bioactive factors in the blood) is at least partially responsible for transducing reductions in age-related endothelial function. To assess whether dolphins have preserved endothelial function with aging because of a protected circulating milieu, we tested if the serum (pool of the circulating milieu) of bottlenose dolphins (Tursiops truncatus) induces the same arterial aging phenotype as the serum of age-equivalent humans. We incubated conduit arteries from young and old mice with dolphin and human serum and measured endothelial function ex vivo via endothelium-dependent dilation to acetylcholine. Although young arteries incubated with serum from midlife/older adult human serum had lower endothelial function, those incubated with dolphin serum consistently maintained high endothelial function regardless of the age of the donor. Thus, studying the arterial health of dolphins could lead to potential novel therapeutic strategies to improve age-related endothelial dysfunction in humans.NEW & NOTEWORTHY We demonstrate that, unlike serum of midlife/older adult humans, age-matched dolphin serum elicits higher endothelial function ex vivo in young mouse carotid arteries, suggesting that the circulating milieu of bottlenose dolphins may be geroprotective. We propose that dolphins are a novel model to investigate potential novel therapeutic strategies to mitigate age-related endothelial dysfunction in humans.