Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults With Coronary Artery Disease: Results of a Pilot Study

Abstract

Rapamycin, an mTOR inhibitor affects senescence through suppression of senescence-associated secretory phenotype (SASP). We studied the safety and feasibility of low-dose rapamycin and its effect on SASP and frailty in elderly undergoing cardiac rehabilitation (CR). 13 patients; 6 (0.5mg), 6 (1.0mg), and 1 patient received 2mg oral rapamycin (serum rapamycin <6ng/ml) daily for 12 weeks. Median age was 73.9±7.5 years and 12 were men. Serum interleukin-6 decreased (2.6 vs 4.4 pg/ml) and MMP-3 (26 vs 23.5 ng/ml) increased. Adipose tissue expression of mRNAs (arbitrary units) for MCP-1 (3585 vs 2020, p=0.06), PPAR-γ (1257 vs 1166), PAI-1 (823 vs 338, p=0.08) increased, whereas interleukin-8 (163 vs 312), TNF-α (75 vs 94) and p16 (129 vs 169) decreased. Cellular senescence-associated beta galactosidase activity (2.2% vs 3.6%, p=0.18) tended to decrease. We observed some correlation between some senescence markers and physical performance but no improvement in frailty with rapamycin was noted. (NCT01649960).

Immunometabolism at the cornerstone of inflammaging, immunosenescence, and autoimmunity in COVID-19

“…In elderly patients with increased senescent PD-1+ T-cells, everolimus (an analog of rapamycin) enhanced immune function, and improved T-cell responses to antigenic stimulation with an acceptable risk/benefit balance [5]. In elderly coronary artery disease patients, rapamycin brought down serum senescence markers through IL-6 suppression [23]. In patients infected with the H1N1 influenza virus, early adjuvant rapamycin therapy over a short period (2 mg/day for 14 days) was significantly linked to enhanced viral clearance, greater improvement in lung injury (i.e.…”

“…IL-1α is the main upstream regulator of SASP, while IL-1β and TGF-β are senescence transmission mediators, and IL-6 and IL-8 reinforce autocrine senescence [22]. In the elderly, especially elderly men, IL-6 is chronically upregulated [23] and its elevation is predictive of mortality [24]. Tissue accumulation of senescent cells and SASP secretion are instrumental in provoking a cytokine storm, that is a major contributor to ARDS and multiple organ dysfunction syndrome [18,19].…”

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

“…Because higher doses of rapamycin typically used in transplant patients are associated with a 20% increased risk of a range of side effects such as mouth sores, rash, or hyperlipidemia, lower doses have been used in anti-aging clinical studies. In one cohort of cardiac rehabilitation patients, ∼60% experienced diarrhea ( Singh et al, 2016 ). Another trial using rapamycin at 1 mg for 8–16 weeks in adults ( n = 28) aged 70–95 years old with stable chronic disease was tolerated reasonably better compared to placebo with small decreases in hemoglobin, and only two participants developed either diarrhea or facial rash.…”

Anti-aging: senolytics or gerostatics (unconventional view)

“…In fact, rapamycin, which does not kill senescent cells, decreases expression of SA-β-gal and p16 [73,74,152]. In the organism, low doses of rapamycin decrease levels of p16 and tend to decrease SA-β-gal activity [153]. Given that current senolytics (F, D+Q) can inhibit mTOR, this scenario is possible.…”