This scientific statement emphasizes the need to view cardiovascular disease, cognitive impairment, and frailty in older adults as manifestations of shared aging processes and provides practical management strategies.
13w ago
Level 1: Clinical Guideline
AlexanderJournal of the American College of Cardiology
This scientific statement emphasizes the need to view cardiovascular disease, cognitive impairment, and frailty in older adults as manifestations of shared aging processes and provides practical management strategies.
Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer’s disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches. Sex-specific biological aging clocks across multiple organs and molecular systems show that female and male aging patterns can differ in organ-specific, disease-relevant ways.
Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer’s disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches. Sex-specific biological aging clocks across multiple organs and molecular systems show that female and male aging patterns can differ in organ-specific, disease-relevant ways.
Three-dimensional branching networks exist throughout biological, natural, and engineered systems as pathways through volumetric space. Segmentation is required to reconstruct these networks for analysis, but minor voxel misclassifications can alter connectivity by falsely disconnecting continuous structures or amplifying spurious branches. Addressing this topological vulnerability requires true 3D segmentation models, since 2D slice-by-slice approaches cannot maintain connectivity across x, y, and z axes. Here, we present DeepBranchAI, a 3D nnU-Net model trained on expert-refined mitochondrial FIB-SEM reference labels as a transferable checkpoint for topology-sensitive segmentation of branching networks. Skeletal-muscle mitochondrial reticulum provides a dense and heterogeneous branching-network training target, and FIB-SEM captures this structure with isotropic nanometer-scale detail. Training on this dataset produced a 3D checkpoint with DSC = 0.942 ± 0.020 across five-fold mitochondrial FIB-SEM validation, providing the basis for subsequent transfer-learning experiments. Transfer learning was evaluated with five-fold cross-validation on paired image/reference-label datasets from 3D-IRCADb venous segmentation, Plant CT roots, and AeroPath airway CT, using continuity-sensitive measures including clDice and absolute connected-component error. Across the external datasets, DeepBranchAI-pretrained fine-tuning had higher mean clDice than scratch nnU-Net. Relative differences in mean clDice were 11.7% for 3D-IRCADb, 5.5% for Plant CT roots, and 1.9% for AeroPath. Mean absolute connected-component error was 25.0% lower for Plant CT roots and 11.7% lower for AeroPath. In 3D-IRCADb, DeepBranchAI-pretrained fine-tuning also had higher mean Dice and clDice than VesselFM, 0.679 versus 0.464 and 0.629 versus 0.360, respectively. The transfer results suggest that training on structurally heterogeneous skeletal-muscle mitochondrial networks can produce 3D features useful beyond the original FIB-SEM domain. Code, trained weights, external-transfer scripts, and validation tables are provided as open-source resources.
Three-dimensional branching networks exist throughout biological, natural, and engineered systems as pathways through volumetric space. Segmentation is required to reconstruct these networks for analysis, but minor voxel misclassifications can alter connectivity by falsely disconnecting continuous structures or amplifying spurious branches. Addressing this topological vulnerability requires true 3D segmentation models, since 2D slice-by-slice approaches cannot maintain connectivity across x, y, and z axes. Here, we present DeepBranchAI, a 3D nnU-Net model trained on expert-refined mitochondrial FIB-SEM reference labels as a transferable checkpoint for topology-sensitive segmentation of branching networks. Skeletal-muscle mitochondrial reticulum provides a dense and heterogeneous branching-network training target, and FIB-SEM captures this structure with isotropic nanometer-scale detail. Training on this dataset produced a 3D checkpoint with DSC = 0.942 ± 0.020 across five-fold mitochondrial FIB-SEM validation, providing the basis for subsequent transfer-learning experiments. Transfer learning was evaluated with five-fold cross-validation on paired image/reference-label datasets from 3D-IRCADb venous segmentation, Plant CT roots, and AeroPath airway CT, using continuity-sensitive measures including clDice and absolute connected-component error. Across the external datasets, DeepBranchAI-pretrained fine-tuning had higher mean clDice than scratch nnU-Net. Relative differences in mean clDice were 11.7% for 3D-IRCADb, 5.5% for Plant CT roots, and 1.9% for AeroPath. Mean absolute connected-component error was 25.0% lower for Plant CT roots and 11.7% lower for AeroPath. In 3D-IRCADb, DeepBranchAI-pretrained fine-tuning also had higher mean Dice and clDice than VesselFM, 0.679 versus 0.464 and 0.629 versus 0.360, respectively. The transfer results suggest that training on structurally heterogeneous skeletal-muscle mitochondrial networks can produce 3D features useful beyond the original FIB-SEM domain. Code, trained weights, external-transfer scripts, and validation tables are provided as open-source resources.
Comparative cellular study demonstrates that reprogramming blood cells into stem cells resets age-related DNA methylation, suggesting epigenetic aging marks are erased during rejuvenation.
Comparative cellular study demonstrates that reprogramming blood cells into stem cells resets age-related DNA methylation, suggesting epigenetic aging marks are erased during rejuvenation.
Background Gait speed is an important indicator of functional status and health outcomes in older adults. Electronic gait mats are common in research, but stopwatches are more feasible in clinical practice. This study compared agreement between single task (ST) gait speed measured by stopwatch and gait mat and described single and dual task (DT) gait performance measured by gait mat. Methods A subset of Atherosclerosis Risk in Communities (ARIC) Study Visit 8 participants completed ST cognitive (serial subtractions), ST gait speed, and DT gait (gait with serial subtractions) on an electronic gait mat; ST gait speed was also assessed by stopwatch. Bland Altman analyses examined agreement between ST gait speed methods. Adjusted linear mixed effects models estimated differences between ST and DT gait parameters. Results Among 364 participants (mean 81.8 years, 54.7% female), faster gait mat gait speeds were associated with a greater discrepancy from stopwatch measurements ( β : −0.24 [95%CI: −0.31, −0.17]), indicating stopwatch underestimation. Participants exhibited mutual interference under DT, walking slower (mean difference in gait speed: −25.0 cm/s [95%CI: −26.8, −23.2]) with shorter (mean difference in step length: −6.2 cm [95%CI: −6.8, −5.6]) and wider steps (mean difference in stride width: 1.6 cm [95%CI: 1.3, 1.9]). Conclusion Gait mat and stopwatch measurements showed acceptable agreement, supporting clinical use. However, greater disagreement at faster speeds suggests gait mats may be more appropriate for faster walking speeds. These findings support future investigations of ST and DT gait performance within ARIC and other aging cohorts, including relationships with cognitive decline, mobility limitations, and adverse health outcomes.
Background Gait speed is an important indicator of functional status and health outcomes in older adults. Electronic gait mats are common in research, but stopwatches are more feasible in clinical practice. This study compared agreement between single task (ST) gait speed measured by stopwatch and gait mat and described single and dual task (DT) gait performance measured by gait mat. Methods A subset of Atherosclerosis Risk in Communities (ARIC) Study Visit 8 participants completed ST cognitive (serial subtractions), ST gait speed, and DT gait (gait with serial subtractions) on an electronic gait mat; ST gait speed was also assessed by stopwatch. Bland Altman analyses examined agreement between ST gait speed methods. Adjusted linear mixed effects models estimated differences between ST and DT gait parameters. Results Among 364 participants (mean 81.8 years, 54.7% female), faster gait mat gait speeds were associated with a greater discrepancy from stopwatch measurements ( β : −0.24 [95%CI: −0.31, −0.17]), indicating stopwatch underestimation. Participants exhibited mutual interference under DT, walking slower (mean difference in gait speed: −25.0 cm/s [95%CI: −26.8, −23.2]) with shorter (mean difference in step length: −6.2 cm [95%CI: −6.8, −5.6]) and wider steps (mean difference in stride width: 1.6 cm [95%CI: 1.3, 1.9]). Conclusion Gait mat and stopwatch measurements showed acceptable agreement, supporting clinical use. However, greater disagreement at faster speeds suggests gait mats may be more appropriate for faster walking speeds. These findings support future investigations of ST and DT gait performance within ARIC and other aging cohorts, including relationships with cognitive decline, mobility limitations, and adverse health outcomes.
Sarcopenia remains underdiagnosed and undertreated, partly because it continues to be mainly conceptualised as a disorder intrinsic to skeletal muscle. Although current definitions incorporate muscle strength and physical performance, they are not intended to explain the integrated physiological processes that underlie age-related impairment of muscle function. In this Personal View, we propose that sarcopenia is more appropriately understood as a manifestation of systemic energetic failure. In this framework, muscle function is considered an emergent property of integrated physiology that progressively deteriorates as ageing disrupts the coordination among energetic demand (determined by neural activation), the delivery of oxygen and metabolic substrates, their mitochondrial transformation into ATP, and their efficient utilisation. The resulting mismatch between physiological demand and available energy manifests clinically as reduced strength in physical performances, increased fatigability, impaired recovery, and mobility disability. Independent lines of evidence have shown that muscle dysfunction reflects a failure of integrated physiological systems rather than isolated tissue degeneration. First, epidemiological data show that muscle strength is more closely linked to disability and mortality than muscle mass. Second, interventional studies show that increasing muscle mass does not reliably improve function. Third, emerging findings indicate that mitochondrial performance is constrained by upstream physiological processes that regulate oxygen and substrate delivery. Reframing sarcopenia considering the failure of these integrated physiological systems has important clinical implications. Fatigability and recovery can provide early indicators of dysfunction, risk stratification should account for multisystem impairment, and effective interventions should focus on restoring coordinated physiological function rather than targeting muscle tissue recovery alone. This framework should be viewed as a physiological hypothesis that integrates current evidence and generates testable predictions regarding the mechanisms, assessment, and treatment of sarcopenia.
Sarcopenia remains underdiagnosed and undertreated, partly because it continues to be mainly conceptualised as a disorder intrinsic to skeletal muscle. Although current definitions incorporate muscle strength and physical performance, they are not intended to explain the integrated physiological processes that underlie age-related impairment of muscle function. In this Personal View, we propose that sarcopenia is more appropriately understood as a manifestation of systemic energetic failure. In this framework, muscle function is considered an emergent property of integrated physiology that progressively deteriorates as ageing disrupts the coordination among energetic demand (determined by neural activation), the delivery of oxygen and metabolic substrates, their mitochondrial transformation into ATP, and their efficient utilisation. The resulting mismatch between physiological demand and available energy manifests clinically as reduced strength in physical performances, increased fatigability, impaired recovery, and mobility disability. Independent lines of evidence have shown that muscle dysfunction reflects a failure of integrated physiological systems rather than isolated tissue degeneration. First, epidemiological data show that muscle strength is more closely linked to disability and mortality than muscle mass. Second, interventional studies show that increasing muscle mass does not reliably improve function. Third, emerging findings indicate that mitochondrial performance is constrained by upstream physiological processes that regulate oxygen and substrate delivery. Reframing sarcopenia considering the failure of these integrated physiological systems has important clinical implications. Fatigability and recovery can provide early indicators of dysfunction, risk stratification should account for multisystem impairment, and effective interventions should focus on restoring coordinated physiological function rather than targeting muscle tissue recovery alone. This framework should be viewed as a physiological hypothesis that integrates current evidence and generates testable predictions regarding the mechanisms, assessment, and treatment of sarcopenia.
reviewJACC Highlight
JUN 2023FormanJournal of the American College of Cardiology
Geroscience and gerotherapeutics offer a novel paradigm to address age-related molecular damage, potentially transforming the management of cardiovascular disease in older adults with multimorbidity and frailty.
Geroscience and gerotherapeutics offer a novel paradigm to address age-related molecular damage, potentially transforming the management of cardiovascular disease in older adults with multimorbidity and frailty.
Senior Lecturer in Human Genetics, St George's University of London · St George's University of London
“
This allowed us to discover 52 regions where 67 genes are located, which we now think are involved in the functioning of the cardiac muscle. We already knew that some of these genes cause serious cardiac diseases, but we did not realise that the majority of them also play a role in the way the heart functions.
52 Genetic Loci Influencing Myocardial Mass
Journal of the American College of Cardiology · Harst et al. ·
JA
Janice Atkins
Research Fellow, University of Exeter Medical School · University of Exeter
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To our knowledge, this is the largest study to show that the longer your parents live, the more likely you are to remain healthy in your sixties and seventies. Asking about parents' longevity could help us predict our likelihood of ageing well and developing conditions such as heart disease, in order to identify patients at higher or lower risk in time to treat them appropriately.
Longer-Lived Parents and Cardiovascular Outcomes
Journal of the American College of Cardiology · Atkins et al. ·
Cohort StudyJACC Highlight
FEB 2011McdermottJournal of the American College of Cardiology
BACKGROUND: The Skeletal Muscle Function Deficit (SMFD) score integrates muscle mass, strength, power and quality into a single construct that evaluates the multidimensional status of muscle health. The aim of the study is to investigate the longitudinal associations of systemic inflammation and caloric intake with SMFD-score trajectories in older adults from the InCHIANTI study. METHODS: Data were obtained from the InCHIANTI population-based longitudinal cohort. A total of 1035 community-dwelling older adults (mean age 74.97 ± 7.39 years; 44.25% men) contributed 3196 repeated observations across four study waves. SMFD-score (range 0-20) was derived from sex-specific quintiles of lower-limb muscle mass, muscle density, grip strength and lower-limb power; participants unable to perform a test received a score of 0 for that component. Interleukin-6 (IL-6) and caloric intake (kcal/day) were assessed at all study waves. Longitudinal associations between time-varying IL-6 tertiles, caloric intake tertiles and SMFD-score trajectories were evaluated using linear mixed-effects models adjusted for baseline age and sex and time-varying multimorbidity and body mass index. RESULTS: Across follow-up, SMFD-score declined significantly from 9.60 ± 4.20 at baseline to 7.07 ± 4.00 at the last wave (p < 0.001), whereas IL-6 increased from 3.65 ± 2.50 pg/mL to 4.39 ± 3.10 pg/mL (p < 0.001). Mean caloric intake showed a non-significant upward trend (1912.83 ± 562.37 to 1976.00 ± 580.54 kcal/day; p = 0.07). In mixed-effects models, higher IL-6 levels were associated with accelerated SMFD decline over time (IL-6 tertile × time interaction β = -0.31 ± 0.02; p < 0.001). Higher caloric intake was associated with higher SMFD-score and a slower functional decline (caloric intake tertile main effect β = 1.19 ± 0.16; p < 0.001; caloric intake tertile × time interaction β = 0.24 ± 0.03; p < 0.001). In the model including the combined IL-6 × caloric intake × time interaction was statistically significant (β = 0.14 ± 0.04; p < 0.001), indicating that higher caloric intake partially attenuated the negative longitudinal association between IL-6 and SMFD-score. CONCLUSIONS: SMFD-score captures longitudinal muscle function decline during aging and reflects the opposing influences of inflammation and caloric intake. These findings support the SMFD-score as a clinically relevant construct for identifying potentially modifiable determinants of muscle health and functional decline in older adults.
13w agoOpen Access
Level 3: Cohort Study
CandeloroJournal of Cachexia Sarcopenia and Muscle
BACKGROUND: The Skeletal Muscle Function Deficit (SMFD) score integrates muscle mass, strength, power and quality into a single construct that evaluates the multidimensional status of muscle health. The aim of the study is to investigate the longitudinal associations of systemic inflammation and caloric intake with SMFD-score trajectories in older adults from the InCHIANTI study. METHODS: Data were obtained from the InCHIANTI population-based longitudinal cohort. A total of 1035 community-dwelling older adults (mean age 74.97 ± 7.39 years; 44.25% men) contributed 3196 repeated observations across four study waves. SMFD-score (range 0-20) was derived from sex-specific quintiles of lower-limb muscle mass, muscle density, grip strength and lower-limb power; participants unable to perform a test received a score of 0 for that component. Interleukin-6 (IL-6) and caloric intake (kcal/day) were assessed at all study waves. Longitudinal associations between time-varying IL-6 tertiles, caloric intake tertiles and SMFD-score trajectories were evaluated using linear mixed-effects models adjusted for baseline age and sex and time-varying multimorbidity and body mass index. RESULTS: Across follow-up, SMFD-score declined significantly from 9.60 ± 4.20 at baseline to 7.07 ± 4.00 at the last wave (p < 0.001), whereas IL-6 increased from 3.65 ± 2.50 pg/mL to 4.39 ± 3.10 pg/mL (p < 0.001). Mean caloric intake showed a non-significant upward trend (1912.83 ± 562.37 to 1976.00 ± 580.54 kcal/day; p = 0.07). In mixed-effects models, higher IL-6 levels were associated with accelerated SMFD decline over time (IL-6 tertile × time interaction β = -0.31 ± 0.02; p < 0.001). Higher caloric intake was associated with higher SMFD-score and a slower functional decline (caloric intake tertile main effect β = 1.19 ± 0.16; p < 0.001; caloric intake tertile × time interaction β = 0.24 ± 0.03; p < 0.001). In the model including the combined IL-6 × caloric intake × time interaction was statistically significant (β = 0.14 ± 0.04; p < 0.001), indicating that higher caloric intake partially attenuated the negative longitudinal association between IL-6 and SMFD-score. CONCLUSIONS: SMFD-score captures longitudinal muscle function decline during aging and reflects the opposing influences of inflammation and caloric intake. These findings support the SMFD-score as a clinically relevant construct for identifying potentially modifiable determinants of muscle health and functional decline in older adults.
Sarcopenia is a major driver of disability, frailty, and loss of independence in ageing populations. Current consensus definitions have shifted from low muscle mass to low muscle strength and impaired physical performance as the defining clinical features. The underlying disease model, however, has remained predominantly muscle-centric, a framing that has generated important advances in muscle biology but has also guided decades of muscle-focused research in which drugs that increase muscle mass have produced inconsistent functional benefits. Muscle mass and intrinsic muscle quality account for an important but incomplete proportion of age-related declines in strength and mobility. Ageing disrupts the entire motor system, from supraspinal centres, spinal circuitry, and peripheral nerves to neuromuscular junctions and muscle, reducing neural drive, coordination, and force generation. We propose reframing sarcopenia as a disease of the ageing motor system. Although existing strength-based and performance-based criteria capture the clinical syndrome, there is scope for improvement. The disease model and diagnostic framework should evolve to reflect the distributed biology of sarcopenia, guiding integrated assessment, mechanistic stratification, and therapies that target both neural and muscular mechanisms. Without this shift, meaningful therapeutic progress will remain challenging.
Sarcopenia is a major driver of disability, frailty, and loss of independence in ageing populations. Current consensus definitions have shifted from low muscle mass to low muscle strength and impaired physical performance as the defining clinical features. The underlying disease model, however, has remained predominantly muscle-centric, a framing that has generated important advances in muscle biology but has also guided decades of muscle-focused research in which drugs that increase muscle mass have produced inconsistent functional benefits. Muscle mass and intrinsic muscle quality account for an important but incomplete proportion of age-related declines in strength and mobility. Ageing disrupts the entire motor system, from supraspinal centres, spinal circuitry, and peripheral nerves to neuromuscular junctions and muscle, reducing neural drive, coordination, and force generation. We propose reframing sarcopenia as a disease of the ageing motor system. Although existing strength-based and performance-based criteria capture the clinical syndrome, there is scope for improvement. The disease model and diagnostic framework should evolve to reflect the distributed biology of sarcopenia, guiding integrated assessment, mechanistic stratification, and therapies that target both neural and muscular mechanisms. Without this shift, meaningful therapeutic progress will remain challenging.
Patients with asymptomatic PAD have worse functional performance and adverse calf muscle characteristics compared to those with typical intermittent claudication, highlighting the hidden severity of asymptomatic disease.
Patients with asymptomatic PAD have worse functional performance and adverse calf muscle characteristics compared to those with typical intermittent claudication, highlighting the hidden severity of asymptomatic disease.
This review examines macrophage influence on extracellular matrix changes in skeletal muscle, highlighting the implications for aging and regeneration.
This review examines macrophage influence on extracellular matrix changes in skeletal muscle, highlighting the implications for aging and regeneration.
