Age-related decline in mobility and cognition are associated with cellular senescence and NAD+ depletion in dogs and people. A combination of a novel NAD+ precursor and senolytic, LY-D6/2, was examined in this randomized controlled trial. Seventy dogs with mild to moderate cognitive impairment were enrolled and allocated into placebo, low dose, or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors.

This randomized controlled blinded trial is one of the first of its kind, evaluating an anti-aging supplement that targets two hallmarks of aging in senior dogs. This clinical trial used a pragmatic approach that included dogs with mild to moderate cognitive impairment who met age, weight and relatively broad health criteria. Dogs were followed to a primary endpoint at 3 months and a secondary endpoint at 6 months.

Fifty-nine dogs completed evaluations at the 3-month primary endpoint, and 51 reached the 6-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint with the largest decrease in the full dose group. No difference was detected between groups using in house cognitive testing. There were no significant differences between groups in changes in measured activity. The proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups, however this difference was not significant. Adverse events occurred equally across groups.

Women live longer than men. This isn't unique to humans, either; we see this trend in a wide range of other animals. Biologists have theorized that the discrepancy in life expectancy between sexes might be partly related to reproduction, but how? Researchers have discovered for the first time that germ cells, the cells that develop into eggs in females and sperm in males, drive sex-dependent lifespan differences in vertebrate animals.

The researchers examined aging in the turquoise killifish, a small, fast-growing freshwater fish with a lifespan of only a few months. As in humans, female killifish live longer than males. However, when the researchers removed the germ cells from these fish, they found that males and females had similar lifespans. The team found that hormonal signaling was very different in females than in males. Female killifish without germ cells had significantly less estrogen signaling, which can shorten lifespan by increasing cardiovascular disease risk. The females also had significantly more growth factor signaling (insulin-like growth factor 1). This made the females grow larger while also suppressing signals within the body important for maintaining health and slowing aging. In contrast, male killifish without germ cells had improved muscle, skin, and bone health. Interestingly, these fish had increased amounts of a substance that activates vitamin D, as well as evidence of vitamin D signaling in their muscles and skin.

The function of germ cells in somatic growth and aging has been demonstrated in invertebrate models but remains unclear in vertebrates. We demonstrated sex-dependent somatic regulation by germ cells in the short-lived vertebrate model Nothobranchius furzeri. In females, germ cell removal shortened life span, decreased estrogen, and increased insulin-like growth factor 1 (IGF-1) signaling. In contrast, germ cell removal in males improved their health with increased vitamin D signaling. Body size increased but was caused by different signaling pathways in the two sexes, i.e., IGF-1 and vitamin D in females and males, respectively. Thus, vertebrate germ cells regulate somatic growth and aging through different pathways of the endocrine system, depending on the sex, which may underlie the sexual difference in reproductive strategies.

An estimated 15.4 million older Americans are unable to walk two to three city blocks. Poor physical function, such as slower walking speed, leads to poor quality of life, institutionalization, incident disability, high healthcare costs, and high mortality in community-dwelling older adults and is considered the "sixth vital sign" for older patients. The underlying mechanisms contributing to slowing gait speed and dismobility are poorly understood. One potential pathway is direct inflammatory effects on muscle and other tissues, leading to wasting and weakness, triggering pathways that contribute to muscle breakdown, fatty infiltration, and fibrosis which can lead to muscle weakness, inefficiency, and mobility disability.

High levels of interleukin-6, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNFα), and TNFα soluble receptors are associated with slow walking speed and frailty primarily in older adults, supporting a role for inflammation on age-related mobility declines during late-life. However, whether chronically elevated levels of inflammation prior to older age, when interventions could be more effective, are associated with late-life mobility has not been well studied. Most studies only examined inflammation measured during older ages and did not consider duration of exposure from midlife, which would provide stronger evidence for causal mechanisms. Furthermore, relating inflammatory markers measured across the mid-to-late-life transition on late-life mobility could identify earlier intervention opportunities, yet studies of inflammation during this critical period are limited, particularly in diverse populations.

Among 4,758 community-dwelling participants in the Atherosclerosis Risk in Communities Study (ARIC), high-sensitivity C-reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990-1992, 47-68 years); at visit 4 (1996-1998, 53-74 years); and with concurrent late-life 4-meter gait speed at visit 5 (2011-2013, 67-88 years, mean 75 years). We examined associations of late-life gait speed with midlife hsCRP (visit 2 continuous and clinically high ≥3 mg/L), with 20-year hsCRP history from midlife (visit 2 to visit 5 average continuous hsCRP and clinically high ≥3 mg/L) and with inflammation accumulation (visits and years with high hsCRP).

High midlife hsCRP was associated with slower late-life gait speed, even among those without chronic conditions in midlife: -4.6 cm/s. Importantly, sustained high hsCRP was associated with a 20-year slowing of -10.0 cm/s among those who never experienced obesity, diabetes, or hypertension over the 20-year period. Inflammation in midlife may contribute to clinically meaningful late-life slowing of gait speed, even among otherwise healthy-appearing adults. Regular monitoring and interventions for inflammation may be warranted from midlife.

Organelle health is vital to a cell's function. Consequently, cells have many mechanisms to repair or eliminate defective organelles. In a recent paper, researchers determined that cardiac myocytes and other cells use secretion to remove mitochondria from the cell when lysosomal degradation is inhibited. Mitochondria generate most of the cell's energy. However, when they become dysfunctional, damaged, or old, mitochondria can turn into pro-death organelles, which produce reactive oxygen species that damage the cell's proteins and DNA. This is a major problem for cardiac myocytes, which rely on the energy produced by mitochondria to contract. Additionally, the body cannot replace these particular cells because they do not divide.

Cells have various quality control mechanisms to detect and repair dysfunctional mitochondria, but when the organelles are too damaged, the cell degrades them using lysosomes. We wanted to determine what happens to the cell when the lysosomes are not functioning well or are overwhelmed, and if there was another pathway to temporarily deal with the damaged mitochondria. This information is of particular importance to patients with Danon's disease, who have mutations in a lysosomal protein that causes cardiomyopathy.

We discovered that fibroblasts and cardiac myocytes secrete mitochondria inside extracellular vesicles (EV) when their lysosomal function is compromised or overwhelmed. This encapsulation ensures that the mitochondria do not elicit a dangerous immune response once outside the cell because of their bacterial origin. The mitochondria-containing EV originate from within multivesicular bodies (MVB), which either deliver the cargo to the lysosomes for degradation or ship everything to the plasma membrane for secretion. We found that Rab7, a protein present on the MVB's outer membrane, is a regulator involved in dictating the fate of the vesicles. We believe that active Rab7 directs the EV toward the lysosomes, but in the absence of this protein or when it is inactive, the cell will traffic the EV to the plasma membrane.

Once cardiac myocytes release the mitochondria-containing EV, resident cardiac macrophages and other cells in the heart internalize the vesicles to degrade them through their lysosomes. The EV do not seem to enter circulation but stay within the heart. Ultimately, this is an alternative garbage disposal pathway used by cells to get rid of dysfunctional and damaged mitochondria when they cannot degrade the organelles in their own lysosomes.

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

The gastrointestinal microbiome is the collection of bacterial cells that reside within the human gastrointestinal tract representing more cells that are contained within the human body, and a metagenome (combined genome of these commensal organisms) that is far larger than the human genome. This community of organisms has been observed to change over the lifespan. Machine-learning-based analysis of published gut microbiome datasets could predict a subject's chronologic age within 5.9 years, although this study was conducted largely independent of any health information. A cross-sectional study across the lifespan (age 1 to over 100) in a Japanese population showed a characteristic microbiome within infants and young children prior to weaning, then a transition to a more diverse microbiome associated with introduction of solid foods. This diverse and dynamic microbiome develops until early adulthood and then becomes relatively stable when it begins to show a decline in diversity after peaking late in life (around 65) and becoming more pronounced in individuals older than 80 years.

Researchers have observed microbiome signatures that became more unique to the individual at extremes of age which may reflect the microbiome becoming tailored to the individual's diet and living environment that perhaps varies less at extremes of age. Intriguingly, very long-lived individuals (over 100 years old) have shown a distinct gut microbiome profile with greater diversity a high abundance of health-associated taxa such as Christensenellaceae and Akkermansia. Although the gut microbiome changes across the lifespan, there are features that have been associated with diseases that develop at different phases of life and contribute to the development of age-related disease later in life. Of particular interest are the microbiomes of "super-agers" who reach extremes of age in relatively good health and have the potential to offer insights into how the microbiome can affect longevity and resistance to age-related diseases.

Although age itself likely contributes to changes in the gastrointestinal microbiome, it is also greatly impacted by the environment in which an individual lives and ages. An exploration of data from metagenomic sequencing of microbiome samples across Europe, Africa, North and South America showed that there were distinct features of each geographic area throughout the lifespan. Much of the literature notes changes in taxa with age that tends to be conserved across different areas of the world. There are, however, notable differences depending on the region in which the study was undertaken. Studies of cohorts in Italy and Ireland have shown decreased abundances of Roseburia with aging, while studies cohorts in Korea and China have reported increases in this genus. Bacteroidetes are generally described as increasing with age, but the converse was observed among healthy older Indonesians. A study of healthy centenarians from India and comparing them with studies previously mentioned from Italy, China, and Japan found unique features in the Indian population such as lower Bacteroidetes, higher Enterobacteriaceae among the Indian cohort. Akkermansia, usually associated with healthy aging, was associated with frailty in a cohort of Chinese older adults.

These discrepancies highlight the extremely complex relationship between the gut microbiome and aging, which is affected not only by the myriad interactions between the host-specific organisms in the microbiome, but also the diet and environment in which the individual ages.

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient-sensing and mitogen-sensing pathway, which promotes cell growth, even though the cell cycle is blocked.

Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin, and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macular degeneration, Alzheimer's and Parkinson's diseases.

Finally, I discuss that extended life span will reveal new causes for aging (e.g. reactive oxygen species, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

Well-documented anti-aging treatments across species of increasing complexity include drugs such as rapamycin, resveratrol, spermidine, chloroquine, and even medications historically employed for treating different diseases, like metformin, which is used in the management of type 2 diabetes. The decreasing magnitude of the positive effect with increasing species complexity in anti-aging treatments is obvious. Thus, we noted the positive effects of metformin decreased from 50% in S. cerevisiae to negligible (if any) effects in humans. Similarly, the effects of resveratrol decreased almost linearly from 70% in S. cerevisiae to 41% in Drosophila, to 30% in C. elegans, to 26% in rodents. The impact of rapamycin on lifespan across species decreased progressively, from 57% in S. cerevisiae to approximately 29% in Drosophila, further declining to 25% in C. elegans, and ultimately reaching 13% in rodents.

The limited translatability between species of increasing complexity can be explained by a number of factors. The effectiveness or significance of the targeted molecule from a pathway might differ in various metabolic scenarios. For example, the anti-aging mechanisms of resveratrol primarily involve ameliorating oxidative stress by scavenging reactive oxygen species (ROS). However, ROS play a more significant role in flying species like Drosophila than in mammals, which may possess additional mechanisms to counteract ROS. Indeed, recent research has revealed a more complex and beneficial role of ROS in regulating metabolism, development, and lifespan.

Second, the weight of targeted signaling pathways differs for a species' general metabolism. Therefore, single mutations that reduce insulin/IGF-1 signaling can significantly increase the lifespan of simple organisms such as C. elegans and D. melanogaster. However, the increased complexity of the pathway, attributed to additional regulators like insulin and growth hormone, has made it challenging to distinguish the roles of each key component in mammalian longevity.

Third, redundancy in pathways is a widespread phenomenon in species of increasing complexity, observed across all forms of life. It has developed as a safeguard against disturbances that might otherwise interfere with essential processes, such as mutations or shifts in the environment. Thus, blocking one pathway does not necessarily impede the cellular or organismal process.

Fourth, as we make progress into research on anti-aging therapies, the challenges posed by the increasing complexity of species remind us that, much like many aspects of biology and medicine, there exists a law of diminishing returns. While the initial interventions may yield significant and noticeable impacts, the subsequent benefits might be less pronounced with the addition of more layers of complexity and control.

Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone-releasing hormone knockout (GHRH-KO) female mice and their littermate controls.

Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH-KO mice, a well-established model of enhanced longevity. While younger GHRH-KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one-third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH-KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH-KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH-KO-induced transcriptional changes.

These findings provide the first evidence of disrupted ceramide metabolism in a long-lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms that influence lifespan extension.

As a principal modulator of the gut microbiome (GM) and weight status, nutritional input holds great therapeutic promise for addressing a wide range of metabolic dysregulation. The GM must regulate its growth rate and diversity in response to nutrient availability and population density. Such maintenance is affected by caloric restriction (CR) coupled with periods of feeding and intermittent fasting (IF). The current study incorporates protein pacing (P), defined as four meals/day consumed evenly spaced every 4 hours, consisting of 25-50 g of protein/meal. Indeed, we have previously characterized a dietary approach of calorie-restricted IF-P combined and P alone.

In this current work, we compare the effects of two low-calorie dietary interventions matched for weekly energy intake and expenditure; continuous caloric restriction on a heart-healthy diet (CR) aligned with current United States (US) dietary recommendations versus our calorie-restricted IF-P diet. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks.

Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P, whereas metabolites associated with a longevity-related metabolic pathway increase with CR. The plasma metabolome analysis revealed the existence of distinct metabolite signatures in IF-P and CR groups, with the convergence of multiple metabolic pathways. Differences indicate GM and metabolomic factors play a role in weight loss maintenance and body composition. This data may inform future GM-focused precision nutrition recommendations using larger sample sizes of longer duration.

Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress, e.g., reactive oxygen species (ROS). Emerging evidence suggests that several fundamental aging mechanisms (e.g., "hallmarks" of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence, and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction.

Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging "hallmarks" to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.

Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF) 2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy.

Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

Liver fibrosis is primarily induced by liver inflammation, which triggers continuous secretion of the extracellular matrix (ECM) by hepatic stellate cells (HSCs). This secretion promotes liver repair, but eventually leads to fibrosis. The treatment of liver fibrosis is a complex process, and the optimal therapeutic strategy is to reverse the fibrotic progression. Conventional cell therapy has demonstrated promise in addressing fibrosis/cirrhosis. However, the direct infusion of hepatocytes faces challenges due to limited hepatocyte sources, poor cell viability, and the requirement for a large number of transplanted parenchymal functional hepatocytes.

Instead of stem cell therapy, liver tissue engineering presents another alternative therapeutic strategy. Tissue-engineering approaches for bioengineering of functional hepatic constructs shows potential to replicate liver physiological structures. However, to restore the normal hepatic architecture and functions, tissue engineering strategies for liver regeneration should position bioengineered hepatic constructs into the defect site of an injured liver instead of heterotopic implantation (subcutaneous or intraperitoneal accesses). Thus, cell sheet engineering technology holds promise because the transplanted cells might be better retained due to preserved contacts between the cells and the ECM.

We developed a hepatic patch by combining decellularized liver matrix (DLM) with the hepatocyte growth factor (HGF)/heparin-complex and evaluated its restorative efficacy. In vitro prophylactic results, the HGF/heparin-DLM patches effectively mitigated CCl4-induced hepatocyte toxicity and restored the cytotoxicity levels to the baseline levels by day 5. Furthermore, these patches restored albumin synthesis of injured hepatocytes to more than 70% of the normal levels within 5 days. In vivo, HGF/heparin-DLM patches attached to the liver and gut exhibited a significant decrease in collagen content (4.44 times and 2.77 times, respectively) and an increase in glycogen content (1.19 times and 1.12 times, respectively) compared to the fibrosis group after 1 week, separately. Thus the newly designed hepatic patch holds promise for regeneration therapy and preventive health care for liver tissue engineering.

There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment can preserve cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats.

Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased the differences between sexes in behavioral stress responsivity, particularly for the initial training on the cued version of the water maze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

The World Health Organization (WHO) has proposed a framework in which healthy ageing is considered not from the perspective of disease but based on an individual's ability to be and do the things they value. This ability is understood to be determined by individual-level attributes - a person's "intrinsic capacity", as well as the environments they inhabit and the interaction between the individual and these environments. Since intrinsic capacity is framed as a continuum that can be considered across the second half of life, it can potentially be used to compare incremental changes among both relatively robust and severely disabled individuals.

We have previously examined intrinsic capacity in two large longitudinal studies of the English and Chinese populations: the English Longitudinal Study on Ageing (ELSA) and the China Health and Retirement Longitudinal Study (CHARLS) Both analyses identified an intrinsic capacity construct that comprises subdomains of cognitive, locomotor, sensory and psychological capacity and a further subdomain labelled vitality, which may represent underlying age-related biological changes and energy balance. The aim of this paper is to conduct a longitudinal analysis of cohort trends in intrinsic capacity in these same studies to determine whether older adults in England and China are experiencing the same, better or worse capacity than people of similar ages in the past.

Our research suggests there have been significant improvements in functioning in more recent cohorts of older people in both England and China. Within ELSA, more recent cohorts entered older ages with higher levels of intrinsic capacity, and subsequent declines were less steep than for earlier cohorts. Improvements were seen in all subdomains. The observed improvements are substantial. To avoid undue extrapolation, we limited our assessment to direct comparisons of capacity in participants of different cohorts at the same age. Currently, the overlap between adjacent cohorts in the ELSA study is 6 years, and participants of non-adjacent cohorts cannot be directly compared. However, even with these limitations, we still found that a 68-year-old ELSA participant born in 1950 had higher intrinsic capacity than a 62-year-old born just 10 years earlier.

Improvement in cognition was even more substantial. When comparing earlier cohorts, additional improvements are observed, although the gains between these cohorts are not quite as large as between the 1940 and 1950 cohorts. Thus, while our models suggest that today's 70-year-olds have the equivalent functioning to substantially younger adults in previous generations (perhaps 70 really is the new 60), our direct assessments can only confirm that 68 is the new 62.

Biological age is a concept that uses bio-physiological parameters to account for individual heterogeneity in the biological processes driving aging and aims to enhance the prediction of age-related clinical conditions compared to chronological age. Although engaging in healthy lifestyle behaviors has been linked to a lower mortality risk and a reduced incidence of chronic diseases, it remains unclear to what extent these health benefits result from slowing the pace of the biological aging process. This short review summarized how modifiable lifestyle factors - including diet, physical activity, smoking, alcohol consumption, and the aggregate of multiple healthy behaviors - were associated with established estimates of biological age based on clinical or cellular/molecular markers, including Klemera-Doubal Method biological age, homeostatic dysregulation, phenotypic age, DNA methylation age, and telomere length.

Individuals who engage in a healthy lifestyle may exhibit a slower pace of biological aging, as their DNA methylation profile and physiological biomarkers are in a healthier state that typically indicates lower risks of mortality and age-related diseases. However, most studies linking lifestyle factors and biological aging are cross-sectional designs, making it difficult to establish causation. Furthermore, it is worth noting that previous research investigating lifestyle factors and biological aging was commonly obtained from specific US cohorts, such as NHANES and the Sister study, probably due to the difficulty of having both biological age measures and comprehensive lifestyle data in other large cohorts. More evidence derived from diverse populations needs to be included.