BackgroundAlmost 75% of US adults are overweight or obese. Though intentional weight loss of as little as 3% improves physical functioning and reduces cardiometabolic risk, most adults are unsuccessful at long-term weight maintenance. Our hypothesis is that intermittent fasting (IF: short periods of intense energy restriction) will reduce weight regain. IF may combat obesity due to its effects on nutrient-sensing signaling pathways and circadian rhythm. The objective of this randomized clinical trial is to test the effectiveness of an intensive body weight management program with and without IF. MethodsIn the Promotion of Successful Weight Management in Overweight and Obese Veterans (POWER-VET) trial (NCT04131647), 154 middle-aged and older adults (50–75 years) who are overweight and obese (BMI: 25–40 kg/m2) and seen at either a Baltimore, MD or San Antonio, TX Veterans Affairs Medical Center will be enrolled. Participants will undergo 12 weeks of weight loss (including a low-calorie heart healthy (HH) diet and exercise). Following weight loss, participants will be randomly assigned to one of two 24-week weight maintenance (WM) interventions: WM alone (continuation of HH diet and exercise) or WM + IF. The primary aim is to determine the effect of WM + IF compared to WM alone on body weight maintenance after intentional weight loss. DiscussionDetermining effective, translatable strategies that minimize weight regain following successful weight loss holds public health relevance. This POWER-VET trial introduces an innovative practice of IF to prevent weight regain after clinically significant weight reduction and could provide evidence-based recommendations to promote this type of intervention in middle aged and older adults.

Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.

This commentary concerns our recent report that prepubertal castration rescued the shorter lifespan of males, using the first mouse line that robustly shows the same shorter longevity with a similar age-variable mortality disadvantage as human males. This model provides a unique opportunity for research to uncover the basis for this clinically important sex difference in aging. Researchers can now identify the hormones involved, the duration of exposure required, and, most important, the cellular and molecular targets, with the ultimate goal of developing therapeutic interventions to enhance health and reduce mortality without castration-compromising reproductive function.

Emerging evidence indicates that errors in RNA processing can causally drive neurodegeneration. Given that RNA produced from expressed genes of all cell types undergoes processing (splicing, polyadenylation, 5' capping, etc.), the particular vulnerability of neurons to deficits in RNA processing calls for careful consideration. The activity-dependent transcriptome remodeling associated with synaptic plasticity in neurons requires rapid, multilevel post-transcriptional RNA processing events that provide additional opportunities for dysregulation and consequent introduction or persistence of errors in RNA transcripts. Here we review the accumulating evidence that neurons have an enhanced propensity for errors in RNA processing alongside grossly insufficient defenses to clear misprocessed RNA compared to other cell types. Additionally, we explore how tau, a microtubule-associated protein implicated in Alzheimer's disease and related tauopathies, contributes to deficits in RNA processing and clearance.

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study. D and Q levels in blood increased in all participants (12.7-73.5 ng ml-1 for D and 3.29-26.3 ng ml-1 for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml-1 with a CSF to plasma ratio of 0.422-0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased (t(4) = 3.913, P = 0.008 and t(4) = 3.354, P = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels (t(4) = -2.338, P = 0.079). In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies. ClinicalTrials.gov identifier: NCT04063124 .

AbstractThe longevity field has received an influx of capital and talent over the past 5 years, but it is unclear where directing these resources would result in the biggest positive impact. We aimed to establish a systematic, rigorous and unbiased way to identify the areas where increased investment would accelerate progress across the whole longevity field the most. To do so, we surveyed ∼400 participants across various sectors of longevity, asking them to 1) identify the major bottlenecks they are experiencing, 2) list their most needed solution, and 3) rate the potential efficacy and barriers to development of various aging intervention strategies. We built a classification system of Bottlenecks and Solutions based on grouping related answers and found the most frequently listed bottlenecks to be 1) lack of validated aging biomarkers; 2) an overall lack of funding; and 3) lack of good models for aging studies. Surprisingly, the most wanted solution was greater availability of large public datasets. Indeed, a common theme across all answers was the need for a new data-centric structure of scientific research, where large datasets are routinely gathered and made available, access walls are removed, protocols are standardized, negative and unpublished data are shared, and AI systems are released on the data for automated discovery. Finally, a lack of regulatory clarity was listed as the biggest barrier to development across all interventions, whereas cellular reprogramming, organ replacement, and genetic medicine (gene therapies and gene editing) were perceived as the intervention strategies with the highest potential for increasing healthy lifespan. We provide these data as a resource for funding agencies, philanthropists, entrepreneurs and newcomers to the field as a means to identify high impact areas to fund and work on.Key takeaways395 Participants were surveyed for their biggest bottlenecks and most needed solutionsTop Bottlenecks: lack of Validated Biomarkers; Overall lack of Funding and Slow & Expensive Models.Top proposed Solutions: more Public Datasets; improved Regulatory Path; and Overall More Funding.Bottlenecks and Solutions vary substantially across industry areas.Rapamycin and calorie restriction are perceived as the most efficacious interventions in the near term.Somatic reprogramming, organ replacement, and genetic medicine are perceived as the most efficacious interventions in the long term (25 years).Sirtuin and NAD targeting therapies are seen as the least efficacious interventions in all time-frames.Across all interventions, Regulatory Issues are perceived as the most severely inhibiting factor in the development of the intervention.

Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.