Hava Shoshana Barkai

Autophagy is widely proposed to decline with age; however, direct evidence across human cell types remains limited. Moreover, it is unclear whether age‐associated changes in autophagy‐gene transcription are accompanied by corresponding changes in autophagic activity, and whether autophagic activity relates to physiological function during aging. We performed transcriptomic and functional autophagy analyses across subject‐matched human cell types from a healthy aging cohort. Autophagy‐related gene expression increased with age in primary dermal fibroblasts and, to a lesser extent, in induced neurons (iNs). However, autophagy flux was cell type‐ and sex‐specific and uncoupled from transcriptional remodeling. Autophagy flux decreased in male fibroblasts, remained stable in female fibroblasts, and increased in female iNs with age. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became increasingly heterogeneous with age and trended higher in older individuals, independent of sex. Associations between autophagy flux and physiological function varied across the adult lifespan; however, in adults aged > 70 years, higher autophagy flux was associated with reduced physical function. In a pilot intervention study, PBMC autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function, suggesting that autophagic activity in PBMCs is responsive to physiological intervention in late life. Together, these findings show that autophagy is remodeled in a cell type‐, sex‐ and physiological function‐dependent manner during aging, challenge the view that autophagy uniformly declines with age, and suggest that elevated autophagy flux in older adults may reflect compensatory responses to age‐associated stress rather than enhanced autophagic capacity.

Autophagy is widely proposed to decline with age; however, direct evidence for this across cell and tissue types in humans remains limited. Furthermore, it remains unknown whether interventions that improve physiological health during aging can modify autophagic activity in humans. Here, we performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort spanning the adult lifespan. RNA-seq of primary dermal fibroblasts and induced neurons (iNs) revealed increased transcription of many autophagy-related genes with age, most markedly in fibroblasts. The impact of age on autophagic activity, measured using autophagy flux assays, was cell type- and sex-dependent, and uncoupled from autophagy-gene transcription. Autophagy flux decreased with age in male fibroblasts, was unchanged in female fibroblasts, and increased in female iNs. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became more heterogeneous with age and trended higher in older individuals, independent of sex. Although autophagy flux levels did not match across different cell types, higher autophagy flux in all cell types was associated with reduced physical function in older adults (≥70 years). Importantly, autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function. These findings indicate that autophagy is regulated in a cell type-, sex-and physiological function-dependent manner during human aging, and highlight PBMC autophagy flux as a potentially modifiable, blood-accessible readout of physiological state in older adults.

Background: Falls and fractures are the leading cause of unintentional injury among older adults, resulting in increased mortality and morbidity, as well as reduced physical function and quality of life. In-person exercise programs aimed at improving strength, balance, and postural control have demonstrated benefits for physical function, quality of life, and fall risk reduction among older adults. Technology-driven approaches can further enhance the accessibility of exercise programs. In particular, digitally delivered programs offer the opportunity to balance risks and benefits while promoting engagement and potentially improving physical function. Objective: The overall aim of this review was to summarize the growing body of research on the efficacy, usability, and safety of these programs in older adults. Methods: MEDLINE via PubMed, the Cochrane Controlled Register of Trials (CENTRAL), and Embase databases were searched for this review. The initial search was conducted in November 2022 and updated in July 2024. Randomized controlled trials, nonrandomized trials, and single-arm pilot studies of at least 6 weeks’ duration reporting digitally delivered exercise for presumptively healthy older adults, taught in real-time (not prerecorded) by a qualified instructor, were included. Interventions targeting specific clinical subpopulations (eg, cardiac rehabilitation, Parkinson disease, chronic obstructive pulmonary disease) were excluded, although common age-related conditions such as hypertension, diabetes, and osteoporosis were included. The review was preregistered via INPLASY (registration number 3773). Results: A total of 4242 studies were screened by title and abstract, with 76 progressing to full-text review. Of these, 23 (30%) met all inclusion criteria, comprising 6 pilot single-arm studies, 5 nonrandomized trials, and 12 randomized trials. Interventions ranged from 6 to 24 weeks, with most lasting 8-12 weeks, and class participation typically occurred 2-3 days per week. Class sizes ranged from as few as 4 to more than 30 participants. Instructor experience varied and included licensed professionals, such as physical therapists, kinesiologists, and certified trainers, as well as laypeople specifically trained for the intervention. A total of 18 out of 23 (78%) studies reported physical outcomes, including balance, strength, and functional measures. Fourteen of these studies reported clinically meaningful improvements following the intervention, most commonly in strength and balance, measured by the 30-second chair stand test and the timed up and go; 20 studies (87%) reported 1 or more observations regarding safety or program usability. Among the studies that provided data on adverse events, most were conducted without injuries or reported only minor injuries. More than 60% of the authors (15/23, 65%) noted in their conclusion statements that participant acceptance of the digital delivery format was high. Conclusions: Overall, these findings demonstrate partial effectiveness in improving physical function related to fall prevention among older adults. Additionally, high attendance, participant enjoyment, and safety highlight the utility of digitally delivered exercise programs for older adults taught in real time. Trial Registration: International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) INPLASY202280097; https://inplasy.com/inplasy-2022-8-0097/

BACKGROUND Falls and fractures are the leading cause of unintentional injury among older adults, resulting in increased mortality and morbidity, as well as reduced physical function and quality of life. In-person exercise programs aimed at improving strength, balance, and postural control have demonstrated benefits for physical function, quality of life, and fall risk reduction among older adults. Technology-driven approaches can further enhance the accessibility of exercise programs. In particular, digitally delivered programs offer the opportunity to balance risks and benefits while promoting engagement and potentially improving physical function. OBJECTIVE The overall aim of this review was to summarize the growing body of research on the efficacy, usability, and safety of these programs in older adults. METHODS MEDLINE via PubMed, the Cochrane Controlled Register of Trials (CENTRAL), and Embase databases were searched for this review. The initial search was conducted in November 2022 and updated in July 2024. Randomized controlled trials, nonrandomized trials, and single-arm pilot studies of at least 6 weeks’ duration reporting digitally delivered exercise for presumptively healthy older adults, taught in real-time (not prerecorded) by a qualified instructor, were included. Interventions targeting specific clinical subpopulations (eg, cardiac rehabilitation, Parkinson disease, chronic obstructive pulmonary disease) were excluded, although common age-related conditions such as hypertension, diabetes, and osteoporosis were included. The review was preregistered via INPLASY (registration number 3773). RESULTS A total of 4242 studies were screened by title and abstract, with 76 progressing to full-text review. Of these, 23 (30%) met all inclusion criteria, comprising 6 pilot single-arm studies, 5 nonrandomized trials, and 12 randomized trials. Interventions ranged from 6 to 24 weeks, with most lasting 8-12 weeks, and class participation typically occurred 2-3 days per week. Class sizes ranged from as few as 4 to more than 30 participants. Instructor experience varied and included licensed professionals, such as physical therapists, kinesiologists, and certified trainers, as well as laypeople specifically trained for the intervention. A total of 18 out of 23 (78%) studies reported physical outcomes, including balance, strength, and functional measures. Fourteen of these studies reported clinically meaningful improvements following the intervention, most commonly in strength and balance, measured by the 30-second chair stand test and the timed up and go; 20 studies (87%) reported 1 or more observations regarding safety or program usability. Among the studies that provided data on adverse events, most were conducted without injuries or reported only minor injuries. More than 60% of the authors (15/23, 65%) noted in their conclusion statements that participant acceptance of the digital delivery format was high. CONCLUSIONS Overall, these findings demonstrate partial effectiveness in improving physical function related to fall prevention among older adults. Additionally, high attendance, participant enjoyment, and safety highlight the utility of digitally delivered exercise programs for older adults taught in real time. CLINICALTRIAL International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) INPLASY202280097; https://inplasy.com/inplasy-2022-8-0097/

Background: Falls remain a major public health problem and a significant cause of preventable injury. Maintaining strength and balance by staying active can prevent falls in older adults, and public health advocates support referral to community exercise programs. Given the growth in use and acceptance of technological interfaces, there remains an interest in understanding the role of a synchronous exercise program designed to improve strength, postural alignment, and balance specifically designed to be delivered in a digital environment with respect to usability and feasibility. Objective: This study aims to design and implement a synchronously delivered digital fall prevention program to adults aged 60 years and older, to understand the usability, feasibility, and attendance. Methods: The “Strong Foundations” program, a 12-week, live, digitally delivered fall-prevention exercise program was informed from different existing in-person exercises and piloted to older adults who were considered a low fall risk by scores of 4 or less from the Centers for Disease Control and Prevention’s (CDC’s) Stopping Elderly Accidents and Deaths Initiative (STEADI) Staying Independent questionnaire. The System Usability Scale (SUS) measured usability and feasibility at the completion of this program, and digital measures of age-related function (timed up and go [TUG] and 30-second chair stand [30 CS]) were collected pre- and postintervention. Data were collected in 2021. Results: A total of 39 older adults were recruited and 38 completed the 12-week program with an average age of 72 years. The average SUS was 80.6, with an 85% attendance rate and an 8.5 (out of 10) self-reported satisfaction score. Digitally collected TUG and 30 CS statistically improved pre- and postintervention by 9% and 24%, respectively; by week 12, 64% (23/36) of participants improved in the timed up and go and 91% (32/35) improved the chair stands. Conclusion: There was excellent usability and acceptability for Strong Foundations, a novel fall-prevention program designed to be delivered digitally and promising improvement of objective measures of fall risk.

Background: Injuries from falls are a major concern among older adults. Targeted exercise has been shown to improve fall risk, and recommendations for identifying and referring older adults for exercise-based interventions exist. However, even when very inexpensive or free, many do not use available fall prevention programs, citing barriers related to convenience and safety. These issues are even greater among older adults residing in rural areas where facilities are less abundant. These realities highlight the need for different approaches to reducing falls in novel ways that increase reach and are safe and effective. Web-based delivery of exercise interventions offers some exciting and enticing prospects. Objective: Our objective was to assess the efficacy of the Strong Foundations exercise program to change markers of physical function, posture, balance, strength, and fall risk. Methods: Strong Foundations is a once weekly (60 minutes), 12-week iterative program with 3 core components: postural alignment and control, balance and mobility, and muscular strength and power. We used a quasi-experimental design to determine changes in physical function specific to balance, postural control, and muscular strength among older adults at low or moderate risk of falling. Results: A total of 55 low-risk and 37 moderate-risk participants were recruited. Participants significantly improved on the 30-second Chair Stand (mean change of 1, SD 3.3 repetitions; P=.006) and Timed Up and Go (mean change of 0.2, SD 0.7 seconds; P=.004), with the moderate-risk group generally improving to a greater degree than the low-risk group. Additionally, Short Physical Performance Battery performance improved significantly in the moderate-risk category (P=.02). The majority of postural measures showed statistically significant improvement for both groups (P<.05). Measures of “relaxed” posture showed improvements between 6% and 27%. When an “as tall as possible” posture was adopted, improvements were ~36%. Conclusions: In this 12-week, iterative, web-based program, we found older adults experienced improvement not only in measures used in clinical contexts, such as the 30-second Chair Stand and Timed Up and Go, but also contextualized gains by providing deeper phenotypical measurement related to posture, strength, and balance. Further, many of the physical improvements were attenuated by baseline fall risk level, with those with the highest level of risk having the greater gains, and, thus, the most benefit from such interventions.

BACKGROUND Injuries from falls are a major concern among older adults. Targeted exercise has been shown to improve fall risk, and recommendations for identifying and referring older adults for exercise-based interventions exist. However, even when very inexpensive or free, many do not use available fall prevention programs, citing barriers related to convenience and safety. These issues are even greater among older adults residing in rural areas where facilities are less abundant. These realities highlight the need for different approaches to reducing falls in novel ways that increase reach and are safe and effective. Web-based delivery of exercise interventions offers some exciting and enticing prospects. OBJECTIVE Our objective was to assess the efficacy of the Strong Foundations exercise program to change markers of physical function, posture, balance, strength, and fall risk. METHODS Strong Foundations is a once weekly (60 minutes), 12-week iterative program with 3 core components: postural alignment and control, balance and mobility, and muscular strength and power. We used a quasi-experimental design to determine changes in physical function specific to balance, postural control, and muscular strength among older adults at low or moderate risk of falling. RESULTS A total of 55 low-risk and 37 moderate-risk participants were recruited. Participants significantly improved on the 30-second Chair Stand (mean change of 1, SD 3.3 repetitions; P=.006) and Timed Up and Go (mean change of 0.2, SD 0.7 seconds; P=.004), with the moderate-risk group generally improving to a greater degree than the low-risk group. Additionally, Short Physical Performance Battery performance improved significantly in the moderate-risk category (P=.02). The majority of postural measures showed statistically significant improvement for both groups (P<.05). Measures of “relaxed” posture showed improvements between 6% and 27%. When an “as tall as possible” posture was adopted, improvements were ~36%. CONCLUSIONS In this 12-week, iterative, web-based program, we found older adults experienced improvement not only in measures used in clinical contexts, such as the 30-second Chair Stand and Timed Up and Go, but also contextualized gains by providing deeper phenotypical measurement related to posture, strength, and balance. Further, many of the physical improvements were attenuated by baseline fall risk level, with those with the highest level of risk having the greater gains, and, thus, the most benefit from such interventions.