Another related new paper:
Cardiac Aging: Molecular Mechanisms and Therapeutic Interventions
Building on this mechanistic framework, we assess a range of interventions, from lifestyle modifications like caloric restriction to targeted pharmaceuticals including rapamycin and senolytics.
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Mammalian target of rapamycin (mTOR), a serine/threonine kinase, plays a pivotal role in orchestrating eukaryotic physiology and has been strongly implicated in the regulation of lifespan and aging[53]. mTOR serves as the catalytic subunit of two distinct protein complexes: mTOR complex 1 (mTORC1) and mTORC2. While both are important, the dysregulation of mTORC1 signaling is particularly central to the aging process. Chronic activation of mTORC1 is a key driver of cellular and tissue aging through several interconnected mechanisms. It activates pathways that promote biomass accumulation and metabolism, including protein synthesis and mitochondrial energy production, which can also increase reactive oxygen species (ROS) production. Critically, mTORC1 actively suppresses autophagy by phosphorylating key regulatory proteins like Ulk1. This impairment of autophagic clearance prevents the removal of damaged cellular components, which contributes to the accumulation of cellular damage, proteotoxic stress, and stem cell exhaustion, ultimately accelerating the “molecular clock” and promoting cellular senescence. Consequently, inhibiting the mTORC1 pathway has emerged as a robust strategy for extending lifespan and improving healthspan. This inhibition—achievable through pharmacological treatment like rapamycin, genetic inactivation, or dietary restriction—has been consistently shown to extend lifespan and enhance physiological performance across various model organisms [54]. The benefits are linked to mitigating the detrimental effects of mTORC1 activation. For example, inhibiting mTORC1 reduces mRNA translation and is linked to the loss of S6K1, a factor that extends lifespan and enhances resistance to a range of age-related diseases, including compromised immunity, motor dysfunction, and insulin resistance [55].
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Moreover, studies suggest that enhanced autophagy facilitates collagen degradation. Research has shown that in fibroblasts from mice deficient in heat shock protein 47 (Hsp47), misfolded procollagen within the endoplasmic reticulum is degraded via the autophagy-lysosomal pathway, as demonstrated by immunoelectron microscopy. Specifically, the use of autophagy inhibitors or deletion of autophagy-related genes significantly increases procollagen aggregates in the endoplasmic reticulum [62]. Conversely, treatment with rapamycin, an autophagy inducer, mitigates this effect by stimulating autophagy [63].
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4.2.3. Rapamycin, an mTOR inhibitor
As a potent mTORC1 inhibitor, rapamycin stands as one of the most validated pharmacological interventions for extending lifespan across multiple species, making its effects on cardiac aging a subject of intense investigation. Preclinical studies have shown significant promise; for instance, rapamycin treatment effectively ameliorates angiotensin II-induced cardiac fibrosis and improves mitochondrial metabolism in aged human cardiac fibroblasts. However, the clinical translation of rapamycin has been hampered by a critical challenge: its off-target inhibition of the mTORC2 complex, which leads to undesirable metabolic and immunological side effects. This limitation underscores a crucial point in anti-aging pharmacology—the need for target specificity. In response to this challenge, the field is now advancing toward the development of novel rapamycin analogues, or ‘rapalogs’, such as DL001, which are engineered to be highly selective for mTORC1 [382]. These next-generation inhibitors hold the potential to deliver the cardioprotective benefits of mTORC1 inhibition while minimizing the adverse effects, representing a more viable path toward clinical application.[383].
mTOR is activated by growth factors and nutrients, which inhibit autophagy and promote protein synthesis. Over time, this may lead to increased cellular stress, including protein aggregation, organelle dysfunction, and oxidative stress. These changes result in the accumulation of damage and a decline in cellular function, thereby contributing to the development of age-related diseases. Studies have shown that the absence of mTOR expression or the introduction of a specific mTOR inhibitor—rapamycin—can extend the lifespan of experimental animals in various models and ameliorate age-related cardiac damage. Thus, mTOR presents itself as an attractive therapeutic target for promoting autophagy and extending lifespan.
Full open access paper:
https://www.sciencedirect.com/science/article/pii/S1043661825003792?via%3Dihub
An AI Summary of the paper:
Here’s a structured summary of the key points from the paper “Cardiac aging: Molecular mechanisms and therapeutic interventions” (Pharmacological Research, 2025):
1. Background & Rationale
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Cardiac aging is a fundamental, non-modifiable risk factor for cardiovascular diseases (CVDs), the world’s leading cause of death.
- Hallmark changes include left ventricular hypertrophy, diastolic dysfunction, fibrosis, endothelial impairment, and arrhythmia risk.
- The paper argues for a shift from treating disease symptoms to targeting the aging process itself, using systems-level interventions.
2. Structural & Functional Alterations
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Organ level: Left ventricular wall thickening, atrial dilation, extracellular matrix remodeling, conduction system fibrosis.
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Functional: Preserved systolic ejection fraction at rest, but impaired diastolic filling and reduced contractile reserve with age.
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Conduction: Loss of pacemaker cells, conduction blocks, atrial fibrillation prevalence rises sharply with age.
3. Core Molecular Mechanisms
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Autophagy dysfunction: Decline in mitophagy, impaired removal of damaged mitochondria, excessive ROS, cell death. mTORC1 hyperactivation suppresses autophagy; rapamycin and caloric restriction counteract this.
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Mitochondrial oxidative stress: ROS overproduction, mtDNA mutations, cristae loss, energy inefficiency → hypertrophy, apoptosis, heart failure. Mitochondria-ER contact sites (MAMs) are key hubs for stress signaling.
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Telomere shortening: Accelerated by oxidative stress, linked to senescence, apoptosis, and worse outcomes in heart failure and atherosclerosis.
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Epigenetic changes:
- DNA hypomethylation and altered histone modifications (e.g., sirtuins protect against hypertrophy/apoptosis).
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Non-coding RNAs: miR-34a promotes apoptosis via PNUTS suppression; miR-21 and miR-1468–3p promote fibrosis; lncRNAs (H19, Sarrah, LUCAT1) and circRNAs (Foxo3, HIPK3) regulate apoptosis, fibrosis, and repair.
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Inflammation & fibrosis: Senescent cells release SASP cytokines (IL-6, TNF-α), activating NF-κB and TGF-β pathways, driving fibrosis and remodeling.
4. Therapeutic Strategies
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Lifestyle: Caloric restriction, exercise, intermittent fasting improve autophagy, mitochondrial health, and vascular function.
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Pharmaceuticals:
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Rapamycin/mTOR inhibitors – extend lifespan, improve diastolic function.
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Senolytics – clear senescent cells, reduce fibrosis/inflammation.
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Antioxidants (e.g., mitochondrial catalase, MitoQ) – target ROS but with mixed clinical results.
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Sirtuin activators (e.g., resveratrol, NAD+ boosters) – epigenetic reprogramming.
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Next-gen approaches:
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Microbiome modulation – gut–heart axis in aging.
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Cell therapies – cardiac stem cell rejuvenation, exosome therapy.
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Gene editing – targeting pro-aging genes or ncRNAs like miR-34a.
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Epigenetic reprogramming – partial Yamanaka factor reprogramming to restore youthful gene expression.
5. Conceptual Framework
- Cardiac aging is not caused by a single pathway, but by an interconnected network of autophagy decline, mitochondrial dysfunction, telomere erosion, epigenetic drift, and chronic inflammation.
- The authors argue for synergistic, multi-target interventions rather than single-drug therapies to truly extend cardiovascular healthspan, not just lifespan.
In essence:
This review maps out how structural, cellular, and molecular processes drive cardiac aging, and highlights therapeutic strategies ranging from caloric restriction and rapamycin to cutting-edge gene editing. It concludes that systems-level, combined interventions will be key to slowing or reversing heart aging and extending healthy longevity.
