搜索结果：The journals of gerontology. Series A, Biological sciences and medical sciences

Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation's effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.

In animal models, caloric restriction (CR) and time-restricted eating (TRE) extend lifespan and healthspan; however, the long-term benefits in humans are unknown. The goal of the Health, Aging and Later-Life Outcomes Pilot (HALLO-P) was to inform the design of a definitive trial to evaluate the long-term effects of CR and TRE in older adults with overweight or obesity. HALLO-P randomized 90 older (≥60 years) adults with obesity or overweight to one of three 9-month interventions: (1) 20% CR delivered in-person; (2) 20% CR delivered remotely (RCR); and (3) 8-hour TRE with ad libitum caloric intake. The degree of sustained CR (by doubly labeled water), the sustainability of TRE, participant retention, and changes in body mass and composition, physical performance, and cardiometabolic risk factors were examined. Participants had a mean (SD) age of 67.2 (4.9) years and BMI of 31.7 (2.9) kg/m2; 62% were female and 83% White. Participant retention was 92%. The mean (SD) percent CR was 4.5% (11.0) in CR and 6.0% (10.3) in RCR. TRE participants reported eating within an 8.5-hour window a median of 84% of days. Mean change in body mass was -4.4, -6.7, and -1.0 kg in CR, RCR, and TRE, respectively. CR and RCR lost fat and lean soft tissue. Chair stand and 400-m walk times improved in RCR and TRE, and there were improvements in glucose and cholesterol levels in all 3 groups. HALLO-P showed that the CR and TRE interventions were feasible and associated with improvements in health status over 9 months despite not achieving the target CR.

There is growing interest in the use of molecular features as predictors of age, age-related disease risk and mortality. A major shortcoming of this field, however, is the lack of suitable translational research models to identify and understand the underlying mechanisms of these predictive biomarkers in human populations. In particular, we lack a system which, like humans, is genetically variable, lives in diverse environments, and experiences age-related chronic conditions treated in the context of a sophisticated health care system. Here, we present results from our analysis of data from the Dog Aging Project (DAP), a long-term longitudinal study of aging in companion dogs. Using longitudinal survival models on data from 937 dogs of the deeply phenotyped Precision Cohort within the DAP, we present the striking finding of a strong, highly significant positive correlation between the effect of individual metabolites on all-cause mortality in humans, and the association of those same metabolites on all-cause mortality in dogs. We also find that across these independent human studies, the biomarkers identified are also highly correlated, strongly suggesting a general signature of mortality within the plasma metabolome across humans, and now in dogs as well. Given the many similarities between dogs and humans with respect to genetics, environment, disease, and disease treatment, and the fact that dogs are so much shorter lived than humans, we argue that dogs represent an extremely valuable translational model in our ongoing effort to understand the underlying molecular causes and consequences of age-related morbidity and mortality in humans.

The Life's Essential 8 (LE8) is a composite metric including 4 health behaviors (diet, physical activity, nicotine exposure, and sleep) and 4 health factors (body mass index, nonhigh-density lipoprotein cholesterol, blood glucose, and blood pressure). This study aimed to describe the cardiovascular health (CVH) metrics promoted by LE8 in nonagenarians and to investigate their relationship with mortality at 5 and 10 years. This study was conducted within the framework of the Mugello Study, a longitudinal survey on nonagenarians living in the Mugello area (Tuscany, Italy). One-hundred and fifty-seven subjects (42 males and 115 females, median age 92 years) were administered a series of validated questionnaires and underwent instrumental examinations and blood withdrawal. CVH metrics were calculated according to LE8 guidelines. Physical activity and sleep duration were quantitatively estimated using a monitor device. In the male group, after 5 and 10 years of follow-up, a higher Health Behavior score was associated with a lower risk of all-cause mortality (HR: 0.963, p = .005 and HR: 0.972, p = .020; after 5 and 10 years). Differently, in the female group, no significant association was observed between the LE8 total score and subscores and different risk of mortality after 5 and 10 years from the interview. These findings highlight the importance of potentially modifiable behaviors in improving survival. They support resource investments to address the needs of individuals in this stage of life and encourage them to be empowered and actively engage in health-promoting behaviors.

This study explores the potential of developing digital biomarkers from wearables for monitoring individuals with Alzheimer's Disease and Related Dementias, focusing on the feasibility of using Apple Watches for tracking health and behaviors in older adults with cognitive impairment. Data collection used the Amissa Health technology stack, which passively collects time-series data from smartwatches and provides a high-frequency cloud database for secure data storage, query, and visualization by clinicians and researchers. The platform consists of (i) AmissaWear, a software app that runs on smartwatches and sends information to a cloud database using a secure API; and (ii) AmissaOrbis, a centralized cloud portal for the collected data. Each participant was provided an Apple Watch configured to collect steps, calories burned, accelerometer and gyroscope readings, heart rate, and sleep information. Seven participants, with cognitive impairment diagnosed by a neurologist, were enrolled in the study from December 2023 through June 2024. The watches successfully collected more than 700 000 observations during the study. Each observation contains data recorded from over a dozen sensors (eg, heart rate, pedometer, gyroscope, and accelerometer). The participants wore Apple Watches for an average of 11.48 hours/day for 84.91% of days during a 6-month period without a decrease in usage over time. Overall, the technology yielded high wear adherence and participation within this pilot. This study demonstrates the feasibility of using widely available Apple Watches for continuous monitoring of individuals with cognitive impairment and provides insights into their daily health and activity patterns, which could aid in future development of digital biomarkers.

Dementia is a terminal illness marked by progressive cognitive decline. This study characterized trajectories of functional status and health care use for people with and without dementia at the end of their life. We used the Health and Retirement Study linked with Medicare claims to generate a series of generalized linear models. Models predicted functional status and health care use for decedents with and without dementia during each month in the last 4&#xa0;years of life (48&#xa0;months). People with dementia have high, sustained functional impairments during the entire last 4&#xa0;years of life. People with dementia have the same predicted average activities of daily living score (1.92) at 17&#xa0;months before death (95% confidence interval [CI]: 1.857, 1.989) as individuals without dementia at 6&#xa0;months before death (95% CI: 1.842, 1.991). Dementia was associated with significantly less hospice during the final 3&#xa0;months of life, with a 12.5% (95% CI: 11.046, 13.906) likelihood of hospice in the last month of life with dementia versus 17.3% (95% CI: 15.573, 18.982) without dementia. Dementia was also associated with less durable medical equipment (p < .001), less home health care (p < .005), and fewer office visits (p < .001). There were not significant differences in likelihood of hospitalization in the last 48&#xa0;months with or without dementia. People with dementia can functionally appear to be at end of life (EOL) for years before their death. Simultaneously, they receive less health care, particularly home health and hospice, in their last months. Models of care that target people with dementia should consider the unique and sustained burden of dementia at EOL.

Metabolic syndrome (MetSyn) is associated with frailty in older adults, with few data among midlife women. We examined MetSyn, including duration, for associations with the development of prefrailty and frailty. The Study of Women's Health Across the Nation is a multiethnic, longitudinal cohort study of women aged 42-52&#x2009;years at the time of enrollment (1996-1997). MetSyn was measured longitudinally, using ATP III criteria, starting at baseline. Pre-frailty and frailty were measured at two later visits (2012/13 and 2015/16) using Fried criteria. Associations of pre-frailty and frailty with prevalent MetSyn, the cumulative number of prior visits with MetSyn, and individual MetSyn criteria were examined using multivariable models. A total of 1769 women were included (mean age 59.7&#x2009;years, SD 3.3). The adjusted odds ratios (aOR) for having pre-frailty or frailty in women with MetSyn compared to those without were 2.77 (95% CI, 2.19-3.50) and 8.73 (95% CI, 5.89-12.95), respectively. Each additional visit a woman met criteria for MetSyn was associated with a higher odds of pre-frailty and frailty (aOR 1.20; 95% CI: 1.14-1.26, and aOR: 1.41; 95% CI: 1.33-1.50, respectively). Individual MetSyn criteria were also associated with the risk of frailty. Among women in this multiethnic cohort, MetSyn was common during midlife and strongly associated with future development of pre-frailty and frailty while women were in their early 60s. Measurement of MetSyn during midlife can help identify women at high risk for developing frailty early in the aging process.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Neurodevelopmental conditions (NDC), including attention deficit/hyperactivity disorder (ADHD) and autism, are associated with increased rates of neurodegenerative diseases, including Alzheimer's disease and related dementias (ADRD) and Parkinson's disease. Such associations are unstudied in diverse populations and while controlling for a range of important covariates. The purpose of this study was to examine the association of ADRD and Parkinson's disease with NDCs in a diverse sample of adults. This case-control study used data from the United States All of Us Research Program 2018-2023 from approximately 600&#xa0;000 adults in the United States. We matched on ADRD and Parkinson's disease status to examine the association of these conditions with NDCs. NDC was more prevalent in ADRD cases than in non-ADRD controls (7.8% vs 2.4%) and among Parkinson's disease cases than non-Parkinson's disease controls (4.5% vs 1.8%). After adjustment for sex, age, education level, body mass index, cardiometabolic conditions, and psychiatric conditions, individuals with ADRD had significantly higher odds of having an NDC compared with controls (adjusted odds ratio, 2.68; 95% CI, 2.40-2.99). Similarly, Parkinson's disease cases had 2.09 times the odds of having an NDC as non-Parkinson's disease controls (95% CI 1.66, 2.59) in adjusted models. As the population of individuals with NDCs ages, and more older adults find themselves in the care of clinicians with expertise in ADRD and Parkinson's disease, it is imperative to understand the support needs of this population, and to provide targets for reducing ADRD prevalence in younger or middle adulthood.

Falls are the leading cause of accidental injury among older adults. Current fall prevention programs are useful but do not target the key variable for injury (ie, impact force). An approach, which has shown promise in robust older adults, is to teach safe-falling strategies to reduce impact forces. In this single-anonymized, pilot randomized controlled trial, we explored the feasibility and preliminary efficacy of a safe-falling program. Twenty-four older adults at risk of injurious falls were randomly assigned either to Falling Safely Training (FAST), a standardized progressive training of safe-falling strategies, or an active control group consisting of evidence-based balance training. Participants underwent a series of experimentally induced falls at baseline, after the 4-week intervention, and 3 months after the intervention. Hip and head acceleration (proxies of impact force) and the number of head impacts experienced during the falls were collected. No adverse events were reported, and 11 of 12 FAST participants completed the intervention. The FAST group had a greater reduction in the number of fall-related head impacts following the intervention (odds ratio&#x2005;=&#x2005;0.10, 95% CI: 0.02, 0.61, p&#x2005;=&#x2005;.012). This improvement coincided with a significant reduction in head acceleration in the FAST group compared to control (between-group mean difference&#x2005;=&#x2005;-9.54 m/s2, p&#x2005;=&#x2005;.028). Hip acceleration decreased significantly in both groups (ps < .001). Teaching older adults at risk of falls safe-falling strategies is safe and feasible and has the potential to minimize fall-related head impacts and reduce fall morbidity.

Life expectancy has increased, but such increase has disproportionally expanded the period of life with diseases. Whether expanding health expectancy (HE), defined as years of life free of chronic diseases, could also affect rate of multimorbidity accumulation is uncertain. Objective: to investigate the dynamic relationship between HE and rate of multimorbidity accumulation and their impact on survival. Four thousand two hundred seventy-four (3511&#x2009;>&#x2009;50 years) participants from the Health and Retirement Study (HRS), healthy at baseline and developing at least one disease overtime were included. Mean baseline age was 55.1 years and average follow-up was 9.4 years. Multimorbidity was operationalized as count of diagnosed diseases from a list of nine chronic conditions. HE was operationalized as years from birth until when the first disease was ascertained, and percentage of life in good health calculated as percentage of life lived free of chronic diseases. Mixed models investigated the association between HE and rate of multimorbidity accumulation, while survival analyses evaluated association with time to death. HE were positively associated with multimorbidity rate (P < .001). Shorter HE and faster multimorbidity rate were independently associated with higher mortality (P < .001). Their interaction was negatively associated with mortality (P < .001). Results were confirmed restricting the analysis to individuals 51 or older and using HRS specific weights. Individuals with longer HE experienced a greater survival, almost regardless of multimorbidity rate, while a positive gradient was found in percentage of life in good health linked to multimorbidity rate. Expanding health expectancy is likely followed by compression of morbidity.

One-third of persons age 60&#x2009;y+ have hearing loss, and hearing loss is a leading preventable risk factor for dementia. We estimated the number of age-associated dementia cases attributable to hearing loss in 2022. We used DeciBHAL, a validated microsimulation of hearing loss that includes age- and sex-specific annual probabilities of incident hearing loss (0.1%-10.4%) and dementia (0.3%-7.1%). Utility decrements are incorporated yearly, based on hearing loss (-0.13 to -0.31) and dementia severity (-0.04 to -0.42), to calculate quality-adjusted life-years (QALYs). We estimated dementia incidence for persons with and without hearing loss by removing the estimated proportion attributable to hearing loss (adjusted incidence risk ratio, 2.0 [range: 1.5-2.5]). We projected two cohorts: the general US population and a hypothetical US population without hearing loss (counterfactual). We applied model-projected dementia incidence and utility among both cohorts to the 74 190 000 US adults >60&#x2009;y and without dementia in 2022. Model-projected incident cases of dementia are 412 000/year (males) and 523 000/year (females). In the simulation without hearing loss, dementia cases/year fall to 339 000 for males and 455 000 for females projecting that 141 000 new dementia cases in 2022 would be attributable to hearing loss. In probabilistic sensitivity analysis, 95% of simulations projected the proportion of dementia cases attributable to hearing loss were 11.5%-23.6% for males and 6.7%-18.7% for females. Hearing loss and associated dementia reduced life-time QALYs by 1.38 for females and 1.69 for males. Model-projected estimates support that hearing loss prevention could substantially reduce new dementia cases and should be a priority.

There is consistent evidence that immune response declines with aging, with wide interindividual variability and a still unclear relationship with the development of frailty. To address this question, we assessed the role of immune resilience (capacity to restore immune functions), operationalized as the neutrophil-to-lymphocytes ratio (NL-ratio) and monocytes-to-lymphocytes ratio (ML-ratio), in the pathway that from robust status shifts to pre-frailty and frailty, and finally to death. The InCHIANTI study enrolled representative samples from the registry lists of 2 towns in Tuscany, Italy. Baseline data were collected in 1998, with follow-up visits every 3 years. The 1&#xa0;453 participants enrolled were assessed and followed for lifestyle, clinical condition, physical performance, clinical, and physiological measures. For the purpose of this analysis, we used only 1&#xa0;022 subjects aged 65 or older at baseline. Participants in the 3 highest deciles of distribution for NL-ratio (>2.44) were more likely to experience a transition from robust to pre-frail, and to overt frailty status. Moreover, NL-ratio (tenth decile&#x2005;>&#x2005;3.53) and ML-ratio (tenth decile&#x2005;>&#x2005;2.02) were both predictors of mortality. These results were independent of chronological age, sex, comorbidities, and chronic low-grade inflammation assessed by high sensitivity C-reactive protein measurement. The 2 leucocytes-derived ratios, NL-ratio and ML-ratio, represent markers of immune resilience and predict changes in physical resilience and mortality. These biomarkers are inexpensive because they are based on data routinely collected in clinical practice and can be used to assess the risk of frailty progression and mortality. Clinical Trials Registration Number: NCT01331512.

This study aimed to dynamically track the priorities and potential research hotspots in the field of heart failure with sarcopenia. Using CiteSpace, we analyzed the literature on heart failure with sarcopenia from the Web of Science database from 1995 to 2022. The analysis encompassed 507 records, revealing an overall upward trend in annual publication volume. Europe and the United States emerged as the primary regions for publishing, particularly driven by contributions from developed countries such as the United States, Germany, and Italy. Productive institutions included the Charite Universitatsmedizin Berlin, University Medical Center Gottingen, the German Center for Cardiovascular Research (DZHK), Universita Cattolica del Sacro Cuore, and the National Institute on Aging (NIA). Noteworthy academic groups have formed around these institutions; von Haehling S, Anker Stefan D, Springer J, and Doehner W frequently collaborated. The core journals that frequently published articles in this area included Circulation, European Heart Journal, and The Journals of Gerontology Series A-Biological Sciences and Medical Sciences. Based on the keyword analysis, we identified three key research areas. First, the diagnosis and definition of sarcopenia emerged as significant themes. Second, researchers have focused on exploring the mechanisms underlying heart failure with sarcopenia, including inflammation, insulin resistance, and oxidative stress. Finally, treatment strategies, such as physical activity and nutritional support, constitute another critical research theme. Furthermore, potential research hotspots within this field include clinical randomized controlled trials, investigations into inflammatory mechanisms, cardiac rehabilitation, studies on physical activity, androgen receptor modulators, and investigations into clinical outcomes such as cognitive impairment.

Large-scale dementia ascertainment for research remains challenging. We demonstrate a method to impute dementia status and onset time using data from the Cardiovascular Health Study (CHS). We used a linear mixed-effects model to estimate individual cognitive trajectories and included the estimates as covariates in an accelerated failure time model used to impute time to incident dementia in the CHS Cognition Study, a sub-study with dementia ascertainment. We calibrated the model in a 60% random sample (n&#x2009;=&#x2009;2000) of eligible participants with CHS Cognition Study dementia classifications and validated the final model in the remaining 40% sample (n&#x2009;=&#x2009;1334). We then imputed dementia onset time and dementia status during follow-up in the full CHS sample, including those without (n&#x2009;=&#x2009;1415) CHS Cognition Study dementia classifications. In the validation sample, relative to the CHS Cognition Study dementia classifications used as the "reference standard," specificity (98.5%), positive predictive value (81.9%), negative predictive value (92.0%), and accuracy (91.3%) were high, while sensitivity was modest (43.8%), with mean imputed onset time &#xb1;1.5&#x2009;years of classified. Performance varied by participant characteristics. Ultimately, 227 (16.0%) of participants without CHS Cognition Study classifications, and 472 (9.9%) of all CHS participants were classified as having dementia according to this approach. The shared parameter approach can be implemented in samples with existing cognitive data and a validation sample with reference-standard dementia adjudication. We found high overall accuracy and higher specificity than sensitivity, similar to reported performance metrics for algorithmic approaches requiring linkage to administrative data.

Whether sex/gender differences in rates of biological aging mediate sex/gender differences in cognition in older adults has not been fully examined. The aim of the current study was to investigate this association. Data from up to 1 928 participants (mean age = 75, standard deviation = 7.04, female = 57%) who took part in the 2016 Harmonized Cognitive Assessment Protocol and Venous Blood Study; substudies of the Health and Retirement Study were included in the current study. The residuals from 4 age-adjusted epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge) were used to measure biological age acceleration. Sex/gender differences in cognition were tested using a series of analyses of covariance. Mediation analyses tested whether the measures of age acceleration accounted for these sex/gender differences, controlling for age, education, smoking status, and white blood cell count. Women outperformed men on measures of verbal learning, verbal memory, visual scanning, and processing speed. No other significant sex/gender differences were identified. Results from mediation analyses revealed that women's slower rates of GrimAge fully accounted for their faster processing speeds and partially accounted for their better performances on verbal learning, verbal memory, and visual scanning measures. None of the other measures of age acceleration were significant mediators. Accounting for sex/gender differences in biological aging may differentiate between cognitive sex/gender differences that are driven by universal (ie, age-related) versus sex-specific mechanisms. More broadly, these findings support the growing evidence that the GrimAge clock outperforms other clocks in predicting cognitive outcomes.

Methionine restriction (MR) has many effects on different molecular and physiological systems and pathways associated with aging. However, these outcomes have often been ambiguous across studies, suggesting the context of outcomes, including tissue type or donor sex, may have a significant impact. We have previously shown that methionine sulfoxide reductase A (MsrA) may have discrete roles on aging physiology under MR. Here, we investigated the effect of MR on putative molecular hallmarks of aging, including mitochondrial function and regulation of the intracellular signal hydrogen sulfide, across tissues and in males and females. We found that females tended to have greater changes in mitochondrial oxygen consumption than males with MR, while the effects of MsrA were context-dependent. Mitochondrial hydrogen peroxide production was decreased by MR in hepatic mitochondria from females and only slightly higher with loss of MsrA in both sexes. In contrast, mitochondrial peroxide production was increased in the kidney with MR regardless of sex or MsrA status. Hydrogen sulfide production capacity was increased only in the liver by MR independent of MsrA, though expression of regulators of hydrogen sulfide generation was changed in a tissue-dependent manner that was not altered by MsrA status. Expression of methionine sulfoxide reductases was also impacted by MR, showing changes in expression in a tissue and sex-dependent manner. These results suggest a complex interaction between tissue, sex, diet, and MsrA status.

Beat-to-beat blood pressure (BP) is an important cardiovascular output and regulated by neurophysiological elements over multiple temporal scales. The multiscale dynamics of beat-to-beat BP fluctuation can be characterized by "BP complexity" and has been linked to age-related adverse health outcomes. We here aimed to examine whether BP complexity mediates the association between arterial stiffness and frailty. This cross-sectional study was completed between January and October 2021. A total of 350 older adults completed assessments for frailty, arterial stiffness (ie, average brachial-ankle pulse wave velocity), and beat-to-beat finger BP. The complexity of beat-to-beat systolic blood pressure (SBP) and diastolic blood pressure (DBP) BP series was measured using multiscale entropy. The relationships between frailty, BP complexity, and arterial stiffness were examined using analysis of variance and linear regression models. The effects of BP complexity on the association between arterial stiffness and frailty were examined using mediation analyses. Compared with non-frail, prefrail, and frail groups had significantly elevated lower SBP and DBP complexity (F > 11, p < .001) and greater arterial stiffness (F = 16, p < .001). Greater arterial stiffness was associated with lower BP complexity (&#x3b2; < -0.42, p < .001). Beat-to-beat SBP and DBP complexity mediated the association between arterial stiffness and frailty (indirect effects >0.28), accounting for at least 47% of its total effects on frailty (mediated proportion: SBP: 50%, DBP: 47%). This study demonstrates the association between BP complexity and frailty in older adults, and BP complexity mediates the association between arterial stiffness and frailty, suggesting that this metric would serve as a marker to help characterize important functions in the older adults.

Frailty indices have been assessed in mouse models for more than a decade, but the effect of sex and strain on frailty outcomes remains poorly understood. Here, we collated and harmonized item-level 31-item clinical frailty index (FI) and lifespan data from 17 independent cohorts, including 1,564 naturally aging mice (690 females, 874 males) across five commonly used mouse strains or substrains: C57BL/6JNIA, C57BL/6N, C57BL/6J, UM-HET3, and Diversity Outbred. A total of 3,665 observations were included across cross-sectional and longitudinal studies, some previously published, with 2,192 observations linked to known age at death. Across all cohorts, FI increased significantly with chronological age, but the rate of frailty accumulation differed by strain. Sex differences in age-associated frailty trajectories were evident only in C57BL/6JNIA mice. Significant strain- and sex-specific differences in both survival and health span were observed, with males generally outliving females, although sex effects varied by strain. FI was strongly associated with lifespan independent of age, although age-dependent effects emerged in specific strains with notable sex-specific patterns. At the level of individual frailty items, most health deficits showed strain-dependent associations with age and lifespan. Collectively, these findings demonstrate that the relationships between frailty, chronological age, and lifespan are strongly modulated by strain and sex. This work highlights the importance of accounting for strain and sex as factors when investigating and utilizing frailty in preclinical models.