Age-related dysregulation of intestinal epithelium fucosylation is linked to an increased risk of colon cancer.

Colon cancer affects people of all ages. However, its frequency, as well as the related morbidity and mortality, are high among older adults. The complex physiological changes in the aging gut substantially limit the development of cancer therapies. Here, we identify a potentially unique intestinal microenvironment that is linked with an increased risk of colon cancer in older adults. Our findings show that aging markedly influenced persistent fucosylation of the apical surfaces of intestinal epithelial cells, which resulted in a favorable environment for tumor growth. Furthermore, our findings shed light on the importance of the host-commensal interaction, which facilitates the dysregulation of fucosylation and promotes tumor growth as people get older. We analyzed colonic microbial populations at the species level to find changes associated with aging that could contribute to the development of colon cancer. Analysis of single-cell RNA-sequencing data from previous publications identified distinct epithelial cell subtypes involved in dysregulated fucosylation in older adults. Overall, our study provides compelling evidence that excessive fucosylation is associated with the development of colon cancer, that age-related changes increase vulnerability to colon cancer, and that a dysbiosis in microbial diversity and metabolic changes in the homeostasis of older mice dysregulate fucosylation levels with age.

Disrupted HSF1 regulation in normal and exceptional brain aging.

Brain aging is a major risk factor for cognitive diseases such as Alzheimer's disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.

Examining the role of different weakness categories for mobility and future falls in older Americans.

BACKGROUND: Recently developed absolute and body size normalized handgrip strength (HGS) cut-points could be used individually and collectively to predict mobility problems and falls. AIMS: We examined the associations of (1) each absolute and normalized weakness cut-point, (2) collective weakness categories, and (3) changes in weakness status on future falls in older Americans. METHODS: The analytic sample included 11,675 participants from the 2006-2018 waves of the Health and Retirement Study. Falls were self-reported. Men were classified as weak if their HGS was < 35.5-kg (absolute), < 0.45 kg/kg (body mass normalized), or < 1.05 kg/kg/m2 (body mass index normalized). While, women were considered weak if their HGS was < 20.0-kg, < 0.337 kg/kg, or < 0.79 kg/kg/m2. Collective weakness categorized those below 1, 2, or all 3 cut-points. The collective weakness categories were also used to observe changes in weakness status over time. RESULTS: Older Americans below each absolute and normalized cut-point had greater odds for future falls: 1.23 (95% confidence interval (CI): 1.15-1.32) for absolute weakness, 1.20 (CI 1.11-1.29) for body mass index normalized weakness, and 1.26 (CI 1.17-1.34) for body mass normalized weakness. Persons below 1, 2, or all 3 weakness cut-points had 1.17 (CI 1.07-1.27), 1.29 (CI 1.18-1.40), and 1.36 (CI 1.24-1.48) greater odds for future falls, respectively. Those in some changing weakness categories had greater odds for future falls: 1.26 (CI 1.08-1.48) for persistent and 1.31 (CI 1.11-1.55) for progressive. DISCUSSION: Collectively using these weakness cut-points may improve their predictive value. CONCLUSION: We recommend HGS be evaluated in mobility and fall risk assessments.

Handgrip Strength Asymmetry and Weakness Are Associated With Future Morbidity Accumulation in Americans.

ABSTRACT: Klawitter, L, Vincent, BM, Choi, BJ, Smith, J, Hammer, KD, Jurivich, DA, Dahl, LJ, and McGrath, R. Handgrip strength asymmetry and weakness are associated with future morbidity accumulation in americans. J Strength Cond Res 36(1): 106-112, 2022-Identifying strength asymmetries in physically deconditioned populations may help in screening and treating persons at risk for morbidities linked to muscle dysfunction. Our investigation sought to examine the associations between handgrip strength (HGS) asymmetry and weakness on accumulating morbidities in aging Americans. The analytic sample included 18,506 Americans aged ≥50 years from the 2006-2016 Health and Retirement Study. Handgrip strength was measured on each hand with a handgrip dynamometer, and persons with an imbalance in strength >10% between hands had HGS asymmetry. Men with HGS <26 kg and women with HGS <16 kg were considered as weak. Subjects reported the presence of healthcare provider-diagnosed morbidities: hypertension, diabetes, cancer, chronic lung disease, cardiovascular disease, stroke, arthritis, and psychiatric problems. Covariate-adjusted ordinal generalized estimating equations analyzed the associations for each HGS asymmetry and weakness group on future accumulating morbidities. Of those included in our study, subjects at baseline were aged 65.0 ± 10.2 years, 9,570 (51.7%) had asymmetric HGS, and 996 (5.4%) were weak. Asymmetry alone and weakness alone were associated with 1.09 (95% confidence interval [CI]: 1.04-1.14) and 1.27 (CI: 1.11-1.45) greater odds for future accumulating morbidities, respectively. Having both HGS asymmetry and weakness was associated with 1.46 (CI: 1.29-1.65) greater odds for future accumulating morbidities. Handgrip-strength asymmetry, as another potential indicator of impaired muscle function, is associated with future morbidity status during aging. Exercise professionals and related practitioners should consider examining asymmetry and weakness with handgrip dynamometers as a simple and noninvasive screening method for helping to determine muscle dysfunction and future chronic disease risk.

Handgrip Strength Asymmetry Is Associated With Limitations in Individual Basic Self-Care Tasks.

This investigation sought to determine the associations between handgrip strength (HGS) asymmetries and limitations in individual activities of daily living (ADL). The analytic sample included 18,468 participants from the 2006 to 2016 waves of the Health and Retirement Study. Those with HGS >10% stronger on either hand had any HGS asymmetry. Individuals with HGS >10% stronger on their dominant or non-dominant hand had dominant or non-dominant HGS asymmetry, respectively. ADL abilities were self-reported. Those with any HGS asymmetry had 1.21 (95% confidence interval [CI] = [1.01-1.46]) greater odds for a toileting limitation and 1.25 (CI = [1.03-1.52]) greater odds for a transferring limitation. Individuals with dominant HGS asymmetry had 1.24 (CI = [1.01-1.53]) greater odds for a transferring limitation. Those with non-dominant HGS asymmetry had 1.39 (CI = [1.01-1.93]) and 1.44 (CI = [1.05-1.96]) greater odds for a bathing and toileting limitation, respectively. HGS asymmetries could help to identify future limitations in specific ADLs.

The estimated prevalence of no reported dementia-related diagnosis in older Americans living with possible dementia by healthcare utilization.

BACKGROUND: Screening for dementia in relevant healthcare settings may help in identifying low cognitive functioning for comprehensive cognitive assessments and subsequent dementia treatment after diagnosis. AIMS: This study sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally-representative sample of older Americans with a cognitive impairment consistent with dementia (CICD) by healthcare utilization. METHODS: The unweighted analytical sample included 1514 Americans aged ≥ 65 years that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. An adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤ 6 had a CICD. Dementia-related diagnosis was self-reported. Respondents indicated if they visited a physician, received home healthcare, or experienced an overnight nursing home stay in the previous two years. RESULTS: The prevalence of no reported dementia-related diagnosis in persons with a CICD who visited a physician was 89.9% (95% confidence interval (CI): 85.4%-93.1%). Likewise, the prevalence of no reported diagnosis in those with a CICD who received home healthcare was 84.3% (CI: 75.1-90.5%). For persons with a CICD that had an overnight nursing home stay, the prevalence of no reported dementia-related diagnosis was 83.0% (CI: 69.1-91.4%). DISCUSSION: Although the prevalence of no reported dementia-related diagnosis in individuals with a CICD differed across healthcare settings, the prevalence was generally high nonetheless. CONCLUSIONS: We recommend increased awareness and efforts be given to dementia screenings in various clinical settings.

A simplified and sensitive immunoprecipitation approach for the analysis of HSF1 in murine liver tissue.

Heat shock factor 1, HSF1, is one of several family members that recognize repeated nGAAn sequences associated with the heat shock element of heat shock and other genes. This transactivator is activated from a monomeric to trimeric form by oxidative, thermal and other stressors. Various studies show that HSF1 levels increase with cancer and decrease with aging and neurodegenerative disorders. It has a role in development as well as infections and inflammation. HSF1 is regulated by post-translational modifications and interactions with other proteins such as HSBP-1. Given its central importance in stress responsivity, various methods have been developed to identify HSF1 and its interacting partners. To date, multiple studies use conventional immunoprecipitation of HSF1 with commercially available antibodies which work well in cell lines but not whole tissue extracts. To remedy this shortfall, we developed a technique to retrieve activated HSF1 with an oligonucleotide link to a magnetic bead. The method captures HSF1 using a DNA sequence specific for HSF1 binding sites on promoter of heat shock genes. Confirmation of tissue derived HSF1 is identified using antibody against HSF1. The magnetic beads conjugated with DNA sequence specific to HSF1 binding was capable of yielding a reproducible band of high signal intensity with low background after native gel electrophoresis and ECL. Thus, the trimeric form of HSF1 can be isolated from tissue with magnetic beads conjugated with a short DNA sequence specific to HSF1 binding. This new method to identify HSF1 is economic, easy, and reproducible and does not require specialized equipment. It overcomes limitations of HSF1 tissue extraction by conventional immunoprecipitation, thus allowing for new approaches to understand HSF1 function in animal and human tissue.•HSF1 is a transcription factor that homotrimerize and binds to a conserved regulatory site, the heat shock element (HSE), consists of repeats of pentameric sequence '5-nGAAn-3' present in the promoters of inducible heat shock protein genes.•This protocol allows isolation of trimeric forms of HSF1 from tissue lysate using magnetic beads conjugated with a short DNA sequence with specific binding to HSF1.•This method is easy, economic and does not require unique instrumentation.

Assessing Additional Characteristics of Muscle Function With Digital Handgrip Dynamometry and Accelerometry: Framework for a Novel Handgrip Strength Protocol.

Maximal handgrip strength (HGS) is a convenient and reliable, but incomplete, assessment of muscle function. Although low HGS is a powerful predictor of poor health, several limitations to maximal HGS exist. The predictive value of HGS is restricted because low HGS is associated with a wide range of unspecified health conditions, and other characteristics of muscle function aside from strength capacity are not evaluated. Current HGS protocol guidelines emphasize the ascertainment of maximal force, which is only a single muscle function characteristic. Muscle function is intrinsically multivariable, and assessing other attributes in addition to strength capacity will improve screenings for age-related disabilities and diseases. Digital handgrip dynamometers and accelerometers provide unique opportunities to examine several aspects of muscle function beyond strength capacity, while also maintaining procedural ease. Specifically, digital handgrip dynamometry and accelerometry can assess the rate of force development, submaximal force steadiness, fatigability, and task-specific tremoring. Moreover, HGS protocols can be easily refined to include an examination of strength asymmetry and bilateral strength. Therefore, evaluating muscle function with new HGS technologies and protocols may provide a more comprehensive assessment of muscle function beyond maximal strength, without sacrificing feasibility. This Special Article introduces a novel framework for assessing multiple attributes of muscle function with digital handgrip dynamometry, accelerometry, and refinements to current HGS protocols. Such framework may aid in the discovery of measures that better predict and explain age-related disability, biological aging, and the effects of comorbid diseases that are amenable to interventions. These additional HGS measures may also contribute to our understanding of concepts such as resilience. Using sophisticated HGS technologies that are currently available and modernizing protocols for developing a new muscle function assessment may help transform clinical practice by enhancing screenings that will better identify the onset and progression of the disabling process.

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice.

How the heat shock axis, repair pathways, and proteostasis impact the rate of aging is not fully understood. Recent reports indicate that normal aging leads to a 50% change in several regulatory elements of the heat shock axis. Most notably is the age-dependent enhancement of inhibitory signals associated with accumulated heat shock proteins and hyper-acetylation associated with marked attenuation of heat shock factor 1 (HSF1)-DNA binding activity. Because exceptional longevity is associated with increased resistance to stress, this study evaluated regulatory check points of the heat shock axis in liver extracts from 12 months and 24 months long-lived Ames dwarf mice and compared these findings with aging wild-type mice. This analysis showed that 12M dwarf and wild-type mice have comparable stress responses, whereas old dwarf mice, unlike old wild-type mice, preserve and enhance activating elements of the heat shock axis. Old dwarf mice thwart negative regulation of the heat shock axis typically observed in usual aging such as noted in HSF1 phosphorylation at Ser307 residue, acetylation within its DNA binding domain, and reduction in proteins that attenuate HSF1-DNA binding. Unlike usual aging, dwarf HSF1 protein and mRNA levels increase with age and further enhance by stress. Together these observations suggest that exceptional longevity is associated with compensatory and enhanced HSF1 regulation as an adaptation to age-dependent forces that otherwise downregulate the heat shock axis.

Handgrip Strength Asymmetry and Weakness Together Are Associated With Functional Disability in Aging Americans.

BACKGROUND: Evaluating handgrip strength (HGS) asymmetry may help to improve the prognostic value of HGS. This study sought to determine the associations of HGS asymmetry and weakness on future activities of daily living (ADL) disability in a national sample of aging Americans. METHODS: The analytic sample included 18,468 Americans aged ≥50 years from the 2006-2016 waves of the Health and Retirement Study. A handgrip dynamometer measured HGS. Those with HGS >10% stronger on either hand were considered as having any HGS asymmetry. Individuals with HGS >10% stronger on their dominant hand were considered as having dominant HGS asymmetry, while those with HGS >10% stronger on their nondominant hand were classified as having nondominant HGS asymmetry. Men with HGS <26 kg and women with HGS <16 kg were considered weak. ADLs were self-reported. Generalized estimating equations were used for analyses. RESULTS: Relative to those with symmetric HGS and no weakness, each HGS asymmetry and weakness group had increased odds for future ADL disability: 1.11 (95% confidence interval [CI]: 1.02-1.20) for any HGS asymmetry alone, 1.42 (CI: 1.16-1.74) for weakness alone, and 1.81 (CI: 1.52-2.16) for both any HGS asymmetry and weakness. Most weakness and HGS asymmetry dominance groups had increased odds for future ADL disability: 1.30 (CI: 1.13-1.50) for nondominant HGS asymmetry alone, 1.42 (CI: 1.16-1.74) for weakness alone, 1.72 (CI: 1.29-2.29) for both weakness and nondominant HGS asymmetry, and 1.86 (CI: 1.52-2.28) for both weakness and dominant HGS asymmetry. CONCLUSIONS: HGS asymmetry and weakness together may increase the predictive utility of handgrip dynamometers.

Handgrip strength asymmetry is associated with future falls in older Americans.

BACKGROUND: Examining handgrip strength (HGS) asymmetry could extend the utility of handgrip dynamometers for screening future falls. AIMS: We sought to determine the associations of HGS asymmetry on future falls in older Americans. METHODS: The analytic sample included 10,446 adults aged at least 65 years from the 2006-2016 waves of the Health and Retirement Study. Falls were self-reported. A handgrip dynamometer measured HGS. The highest HGS on each hand was used for determining HGS asymmetry ratio: (non-dominant HGS/dominant HGS). Those with HGS asymmetry ratio < 1.0 had their ratio inverted to make all HGS asymmetry ratios ≥ 1.0. Participants were categorized into asymmetry groups based on their inverted HGS asymmetry ratio: (1) 0.0-10.0%, (2) 10.1-20.0%, (3) 20.1-30.0%, and (4) > 30.0%. Generalized estimating equations were used for the analyses. RESULTS: Every 0.10 increase in HGS asymmetry ratio was associated with 1.26 (95% confidence interval (CI) 1.07-1.48) greater odds for future falls. Relative to those with HGS asymmetry 0.0-10.0%, participants with HGS asymmetry > 30.0% had 1.15 (CI 1.01-1.33) greater odds for future falls; however, the associations were not significant for those with HGS asymmetry 10.1-20.0% (odds ratio: 1.06; CI 0.98-1.14) and 20.1-30.0% (odds ratio: 1.10; CI 0.99-1.22). Compared to those with HGS asymmetry 0.0-10.0%, participants with HGS asymmetry > 10.0% and > 20.0% had 1.07 (CI 1.01-1.16) and 1.12 (CI 1.02-1.22) greater odds for future falls, respectively. DISCUSSION: Asymmetric HGS, as a possible biomarker of impaired neuromuscular function, may help predict falls. CONCLUSIONS: We recommend that HGS asymmetry be considered in HGS protocols and fall risk assessments.

A molecular perspective on age-dependent changes to the heat shock axis.

Aging is a complex process associated with progressive damage that leads to cellular dysfunction often accompanied by frailty and age-related diseases. Coping with all types of physiologic stress declines with age. While representing a primordial, cross-species response in poikilo- and homeotherms, the age-dependent perturbation of the stress response is more complex than previously thought. This short review examines how age influences the stress axis at multiple levels that involve both activating and attenuating pathways.

Multifactorial Attenuation of the Murine Heat Shock Response With Age.

Age-dependent perturbation of the cellular stress response affects proteostasis and other key functions relevant to cellular action and survival. Central to age-related changes in the stress response is loss of heat shock factor 1 (HSF1)-DNA binding and transactivation properties. This report elucidates how age alters different checkpoints of HSF1 activation related to posttranslational modification and protein interactions. When comparing liver extracts from middle aged (12 M) and old (24 M) mice, significant differences are found in HSF1 phosphorylation and acetylation. HSF1 protein levels and messenger RNA decline with age, but its protein levels are stress-inducible and exempt from age-dependent changes. This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of HSF1 protein levels that are low in neurodegeneration and elevated in cancer.

Weakness May Have a Causal Association With Early Mortality in Older Americans: A Matched Cohort Analysis.

OBJECTIVES: Quantifying the association between muscle weakness and mortality with carefully matched cohorts will help to better establish the impact of weakness on premature death. We used a matched cohort analysis in a national sample of older Americans to determine if those who were weak had a higher risk for mortality compared with control groups with incrementally higher strength capacities. DESIGN: Longitudinal panel. SETTING: Detailed interviews that included physical measures were conducted in person, whereas core interviews were often performed over the telephone. PARTICIPANTS: Data from 19,729 Americans aged at least 50 years from the 2006-2014 waves of the Health and Retirement Study were analyzed. MEASURES: A handgrip dynamometer was used to assess handgrip strength (HGS) in each participant. Men with HGS <26 kg were considered weak, ≥26 kg were considered not weak, and ≥32 kg were considered strong. Women with HGS <16 kg were classified as weak, ≥16 kg were classified as not-weak, and ≥20 kg were classified as strong. The National Death Index and postmortem interviews determined the date of death. The greedy matching algorithm was used to match cohorts. RESULTS: Of the 1077 weak and not-weak matched pairs, 401 weak (37.2%) and 296 not-weak (27.4%) older Americans died over an average 4.4 ± 2.5-year follow-up. There were 392 weak (37.0%) and 243 strong (22.9%) persons who died over a mean 4.5 ± 2.5-year follow-up from the 1057 weak and strong matched pairs. Those in the weak cohort had a 1.40 [95% confidence interval (CI) 1.19, 1.64] and 1.54 (CI 1.30, 1.83) higher hazard for mortality relative to persons in the not-weak and strong control cohorts, respectively. CONCLUSIONS AND IMPLICATIONS: Our findings may indicate a causal association between muscle weakness and mortality in older Americans. Health care providers should include measures of HGS as part of routine health assessments and discuss the health risks of muscle weakness with their patients.

Integrating Geriatrics Knowledge into a Medical Student Clerkship Using Twitter Poll.

A controlled, prospective, 2-year cohort observational study was conducted to test whether weekly geriatric questions delivered through Twitter Poll could improve geriatrics knowledge during an internal medicine clerkship for third-year medical students. Pre- and post-rotation test results used a modified University of California, Los Angeles geriatric knowledge test that included questions linked to 26 Association of American Medical Colleges geriatric competencies for medical students. Data were analyzed using a general linear model repeated-measure design and Student t-test. The primary outcome showed that Twitter Poll participants had more than twice the geriatrics knowledge (p = .002) than students who did not use Twitter Poll. Subset analysis showed different test performances according to sex (p = .03), training site (p = .002), and cohort (p = .003). This study is the first demonstration of Twitter Poll efficacy in medical education and raises questions about whether it could be even more effective if linked to spaced timing of didactic content or supported by annotated answers to geriatrics questions. J Am Geriatr Soc 66:2389-2393, 2018.

Promoting Seniors' Health With Home Care Aides: A Pilot.

Purpose: Regular physical activity (PA) benefits older adults. However, frail older adults lack opportunities to be physically active. This pilot study aimed to test and enhance the feasibility of a PA program delivered by home care aides (HCAs) for community-dwelling older adults in a Medicaid-funded home care setting and to generate preliminary efficacy and cost data. Design and Methods: HCAs were trained to deliver a brief motivational enhancement and three chair-bound movements to motivate their older clients to do PA daily and to help maintain their independence in the community. Mixed methods were used to evaluate clients' function and health before and after the 4-month intervention. Results: Clients' daily activity function and health outcomes (physical fitness, self-rated health, pain interference, and fear of falling) improved significantly. The program was well-received by clients (N = 54) and their HCAs (N = 46) as indicated by high retention rates among client participants (93%) and remarks provided by clients. Implications: Building PA into the everyday care of older adults and the routine work of HCAs is feasible. The intervention has the potential for further implementation and dissemination.

Co-learning with home care aides and their clients: collaboratively increasing individual and organizational capacities.

Changes in health care provide unprecedented opportunities for collaboration across research, education, and practice for the common goal of enhancing the well-being of older adults and their caregivers. This article describes how a pilot project, Promoting Seniors' Health with Home Care Aides, has synergistic education, research, and practice effects that enhance individual and organizational capacities. This pilot is an innovative partnership with home care aides to deliver a safe physical activity program appropriate for frail seniors in a real-life public home care program. The intervention and research occur in older adults' homes and thus provide rare opportunities for the research team and partners to learn from each other about dynamics of home care in older adults' life contexts. Co-learning is essential for continuous quality improvement in education, research and practice. The authors propose to establish "teaching home care" to ensure ongoing co-learning in gerontology and geriatrics.

Impact of Cognitive Training on Balance and Gait in Older Adults.

OBJECTIVES: Cognitive processing plays an important role in balance and gait and is a contributing factor to falls in older adults. This relationship may be explained by the fact that higher order cognitive functions such as executive functions are called upon while walking. The purpose of this study was to examine whether a cognitive training intervention leads to significant improvements on measures of balance and gait. METHOD: This randomized trial tested whether cognitive training over 10 weeks improves balance and gait in older adults. Participants were randomly assigned to a computer-based cognitive training intervention or measurement-only control. Outcomes included Timed Up and Go (TUG), gait speed, and gait speed with a cognitive distraction. Data were analyzed using analysis of covariance models with change scores. RESULTS: Participants' (N = 51) average age was 82.7 for those randomized to intervention and 81.1 for those randomized to control. After 10 weeks, intervention group participants performed significantly better than controls on the TUG. When the cohort was limited to those categorized as slow walkers (baseline 10-m walk ≥ 9 s), intervention participants performed significantly better than controls on TUG and distracted walking. DISCUSSION: Cognitive training slows degradation of balance and improves gait while distracted, rendering it a promising approach to falls prevention.

Relation of high heart rate variability to healthy longevity.

The population's aging underscores the need to understand the process and define the physiologic markers predictive of healthy longevity. The findings that aging is associated with a progressive decrease in heart rate variability (HRV), an index of autonomic function, suggests that longevity might depend on preservation of autonomic function. However, little is known about late life changes. We assessed the relation between autonomic function and longevity by a cross-sectional study of HRV of 344 healthy subjects, 10 to 99 years old. The HRV was determined from 24-hour Holter records, using 4 time domain measures of HRV (the root mean square of the successive normal sinus RR interval difference [rMSSD], percentage of successive normal sinus RR intervals >50 ms [pNN50], standard deviation of all normal sinus RR intervals during a 24-hour period [SDNN], and standard deviation of the averaged normal sinus RR intervals for all 5-minute segments [SDANN]). Autonomic modulation of the 4 measures differs, permitting distinctions between changes in HRV-parasympathetic function, using rMSSD and pNN50, and HRV-sympathetic function using SDNN and SDANN. Decade values were compared using analysis of variance and t-multiple comparison testing. The HRV of all measures decreases rapidly from the second to fifth decades. It then slows. The HRV-sympathetic function continues to decrease throughout life. In contrast, the decrease in HRV-parasympathetic function reaches its nadir in the eighth decade, followed by reversal and a progressive increase to higher levels (p <0.05), more characteristic of a younger population. In conclusion, healthy longevity depends on preservation of autonomic function, in particular, HRV-parasympathetic function, despite the early age-related decrease. The eighth decade reversal of the decrease in HRV-parasympathetic function and its subsequent increase are key determinants of longevity. Persistently high HRV in the elderly represents a marker predictive of longevity.