Girish Harinath’s research while affiliated with Concordia University Ann Arbor and other places

Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the dynamics of low-dose rapamycin bioavailability, and any differences in bioavailability for different formulations (e.g., compounded or commercial), remain poorly understood. We thus explored rapamycin bioavailability in two real-world cohorts to begin providing a foundational understanding of differences in effects between formulations over time. The small trial study cohort was utilized to explore the blood rapamycin levels of commercial ( n = 44, dosages 2, 3, 6, or 8 mg) or compounded ( n = 23, dosages 5, 10, or 15 mg) rapamycin 24 h after dose self-administration. Results suggested dose-to-blood level relationships were linear for both formulations, though compounded had a lower bioavailability per milligram of rapamycin (estimated to be 31.03% of the same dose of commercial). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals over time demonstrated relative consistency. Extending exploration to 316 real-world longevity rapamycin users from the AgelessRx Observational Research Database produced similar findings, and additionally suggested that blood rapamycin levels peak after 2 days with gradual decline thereafter. Taken together, our findings suggest that individualized dosing and routine monitoring of blood rapamycin levels should be utilized to ensure optimal dosing and efficacy for healthy longevity.

Background Low-dose rapamycin promotes longevity in mice, but clinical safety and longevity data effects in humans remain limited. Objectives Evaluate the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Design This decentralized double-blinded, randomized, placebo-controlled trial ( NCT04488601 , registered 2020-07-28) was performed over 48 weeks. Participants received placebo, 5mg or 10mg compounded rapamycin (equivalent to 1.43mg or 2.86mg of generic formulations) weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring. Results Adverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (η p ² =0.001, p =0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (ε ² =0.202, p =0.013) and self-reported pain (ε ² =0.168, p =0.015) improved significantly for women using 10mg rapamycin. Trends of improvement in bone mineral density were observed in males using 10mg rapamycin (ε ² =0.221, p =0.061), but no other significant effects were observed. Conclusions Low-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.

Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the bioavailability of generic and compounded rapamycin at longevity doses in normative aging individuals remains unknown. We conducted a retrospective, real-world study determining the 24-hour blood rapamycin levels to establish the relative bioavailability, dose-to-blood level linearity and inter-individual heterogeneity in a normative aging cohort. Participants received either compounded rapamycin (n = 23, dosages 5, 10, or 15 mg) or generic rapamycin (n= 44, dosages 2, 3, 6, or 8 mg) once per week, and were asked to obtain a sirolimus level blood draw 24 hours after dose self-administration. Similar blood rapamycin levels and a linear dose-to-blood level relationship were observed for both formulations, although a higher bioavailability per milligram of rapamycin was noted for the generic formulation (compounded averaged 0.287 (28.7%) bioavailability relative to generic rapamycin in (ng/mL) / mg rapamycin). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals demonstrated high test-retest reliability. As we detected no significant association between bioavailability and measures of body mass index (BMI), sex, age, or length of time taking rapamycin, we suggest that individualized dosing and routine monitoring of blood rapamycin levels should be applied to ensure optimal longevity efficacy. Finally, we contextualize our data with a brief review of the literature on the currently available knowledge of rapamycin's bioavailability in normative aging populations, and provide implications for the clinical use of rapamycin in longevity medicine moving forward.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted. In this pilot study, we assessed whether treatment with low-dose naltrexone (LDN, 4.5 mg/day) and supplementation with NAD + through iontophoresis patches could improve fatigue symptoms and quality of life in 36 patients with persistent moderate/severe fatigue after COVID-19. We detected a significant increase from baseline in SF-36 survey scores after 12 weeks of treatment (mean total SF-36 score 36.5 [SD: 15.6] vs. 52.1 [24.8]; p < 0.0001), suggestive of improvement of quality of life. Furthermore, participants scored significantly lower on the Chalder fatigue scale after 12 weeks of treatment (baseline: 25.9 [4.6], 12 weeks: 17.4 [9.7]; p < 0.0001). We found a subset of 52 % of patients to be responders after 12 weeks of treatment. Treatment was generally safe, with mild adverse events previously reported for LDN, which could be managed with dose adjustments. The iontophoresis patches were associated with mild, short-lived skin irritation in 25 % of patients. Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19. Larger randomized controlled trials will have to confirm our data and determine which patient subpopulations might benefit most from this strategy.

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies—for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Aging is characterized by declining health that results in decreased neuromuscular function and cellular resilience. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of anti-aging interventions. Here we combined survival under thermal and oxidative stress with swimming performance, to evaluate health effects across a nematode genetic diversity panel for three compounds previously studied in the Caenorhabditis Intervention Testing Program - NP1, propyl gallate, and resveratrol. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. Additionally, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible aging interventions.