This 2025 Frontiers in Immunology review reframes cardiovascular aging as a coordinated failure of stress-response pathways across endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, and immune lineages. The authors synthesize genomic, molecular, and preclinical data to argue that vascular and myocardial decline is not a diffuse “wear and tear” phenotype but a targetable network driven by senescence, impaired autophagy, mitochondrial derangement, and sterile inflammation.
Mechanistically, three axes unify cardiovascular aging. First, mTORC1 overactivation and insufficient AMPK–ULK1 signaling suppress autophagy, enabling accumulation of dysfunctional mitochondria, proteotoxic aggregates, and lipid peroxides. Second, mitochondrial ROS and mtDNA leakage activate cGAS–STING, linking energy decline to SASP-driven chronic inflammation and endothelial injury. Third, senescent endothelial and VSMC populations secrete cytokines (IL-6, IL-1β, TGF-β) that accelerate fibrosis, arterial stiffening, and plaque instability. These processes manifest early in the vasculature, making cardiovascular tissues a primary aging bottleneck.
The review’s novelty lies in synthesizing cell-type–specific vulnerabilities (e.g., endothelial autophagy deficits vs. cardiomyocyte mitochondrial fragmentation), integrating immune aging into cardiovascular dysfunction, and detailing next-generation interventions—including uPAR-targeted senolytic CAR-T cells, JAK–STAT SASP blockade, senolytic flavonoids, and mTOR-targeted strategies that overlap with systemic longevity interventions.
Potentially Actionable insights for research-literate biohackers
- Track biomarkers: ApoB, LDL-C, hs-CRP, IL-6, GDF-15, NT-proBNP, pulse-wave velocity, VO₂max, and epigenetic/inflammatory clocks (DunedinPACE, iAge).
- Target mTOR/AMPK balance: Consider IF/CR, endurance training, sauna/heat stress, and—with medical supervision—rapalog or metformin protocols that promote autophagy without chronic immunosuppression.
- Senolytic exploration (high-risk/experimental): Intermittent D+Q or fisetin regimens; evaluate vascular effects through PWV, endothelial function (FMD), and hs-CRP changes.
- Stacking hypotheses: Combine GLP-1RA or SGLT2i (cardiometabolic benefits; mitochondrial protection) with autophagy-promoting routines; avoid overlapping immunosuppressive mechanisms.
- Dose-timing ideas: Time autophagy-promoting interventions (fasting, rapalog pulses) away from high-intensity training days to avoid impaired adaptation.
- Cognition/vascular coupling: Monitor executive function and sleep metrics—vascular aging correlates strongly with cognitive decline.
Cost-effectiveness considerations
Most ROI resides in cardiometabolic risk control (statins, antihypertensives, GLP-1RA/SGLT2i, aerobic capacity). Rapalogs and senolytics offer uncertain marginal gains with higher risk and cost. Cell therapies and CAR-T are scientifically promising but economically prohibitive and clinically unvalidated for lifespan.
Critical limitations
Evidence derives primarily from rodent and in vitro systems with heterogeneous senescence markers, inconsistent dosing paradigms, and limited longitudinal data. No human trials yet demonstrate reduced cardiovascular events through senolytics or autophagy-targeting interventions. Cardiovascular autophagy and SASP biomarkers remain poorly standardized. Translation requires mechanistically stratified human studies integrating imaging, immune profiling, and multi-omics.
Source Paper (open access): Mechanisms of aging in the cardiovascular system: challenges and opportunities , Frontiers in Immunology