The Impact of Sildenafil on Aging Processes and Quality of Life in Older Adults

1.1 Maintenance of the NO–cGMP Signaling Pathway

With advancing age, the bioavailability of nitric oxide (NO) and the activity of the NO–cyclic guanosine monophosphate (cGMP) signaling pathway decline. This decrease is partly attributed to increased expression of phosphodiesterases, which break down cGMP.[1,2] As a result, older insectioniduals often experience impaired vasodilation, increased arterial stiffness, higher blood pressure, and heightened inflammation.[2] By inhibiting PDE5, sildenafil prevents the degradation of cGMP, thereby restoring cGMP levels in tissues and improving endothelial function.

In a mouse model of accelerated aging, chronic sildenafil administration significantly improved endothelium-dependent, NO-mediated vascular relaxation and mitigated age-related vascular dysfunction.[3] Notably, these improvements occurred without significantly altering systemic blood pressure, suggesting a direct “anti-aging” effect on vascular walls.[4] Researchers posit that such findings have important clinical implications for preventing age-related cardiovascular diseases.

As we age, our blood vessels become stiffer, which can lead to higher blood pressure and inflammation, and some research suggests that sildenafil may help by supporting the natural processes that keep them flexible.

1.2 Activation of Cellular Longevity Pathways

Raising intracellular cGMP through PDE5 inhibition can activate signaling cascades that bolster stress resistance and metabolic health. Specifically, sildenafil has been shown to upregulate sirtuin-1 (SIRT1) and the PGC-1α coactivator via the protein kinase G (PKG) and CREB pathway.[5] These molecules are sometimes referred to as “longevity genes” due to their roles in mitochondrial biogenesis, antioxidant enzyme production, and cellular damage repair. Studies also report that sildenafil reduces β-amyloid formation, oxidative stress, and inflammation in animal models, while enhancing mitochondrial generation.[5,6] Thus, pharmacologically enhancing the NO–cGMP axis with sildenafil may decelerate certain aspects of cellular aging by supporting energy metabolism and suppressing chronic inflammation.

2.1 Cardiovascular Benefits in Older Adults

As a vasodilator, sildenafil improves endothelial function and blood flow—key considerations when addressing age-related vascular changes. Large-scale cohort data in older men with cardiovascular risk factors or established heart disease suggest that PDE5 inhibitors, including sildenafil, are associated with favorable outcomes. In a cohort of more than 500,000 patients with erectile dysfunction, the use of sildenafil or tadalafil over three years correlated with a significant reduction in all-cause mortality (relative risk ~0.76 for sildenafil) and a lower incidence of major cardiovascular events (myocardial infarction, stroke, and thromboembolic events).[7]

Similarly, in approximately 43,000 men who survived a myocardial infarction, subsequent treatment of ED (primarily with sildenafil) was linked to a 33% reduction in mortality over the follow-up period, compared to those who did not receive PDE5 inhibitors.[8] Moreover, the risk of heart failure hospitalizations was about 40% lower among patients on sildenafil. While these epidemiological findings do not definitively prove causation, they point to a possible cardioprotective and lifespan-enhancing effect that warrants further investigation in randomized controlled trials.

2.2 Mechanisms of Cardioprotection

Several mechanisms have been proposed to explain sildenafil’s potential cardiovascular benefits. By enhancing cGMP signaling, sildenafil improves coronary blood flow and reduces cardiac workload, potentially preventing endothelial dysfunction, atherosclerosis, and thrombosis.[3] Animal studies show that PDE5 inhibition decreases myocardial hypertrophy and fibrosis, improves vascular relaxation, and may slow the progression of hypertension and ischemic injury. Collectively, these actions could mitigate what is sometimes referred to as “vascular aging,” a gradual deterioration of the cardiovascular system that is a major contributor to reduced longevity.

3.1 Potential for Neuroprotection

Interest in sildenafil as a neuroprotective agent has grown due to its ability to enhance cerebral blood flow and positively influence molecular pathways implicated in Alzheimer’s disease (AD). Sildenafil crosses the blood–brain barrier and exerts vasodilatory effects on cerebral blood vessels. A large-scale in silico and epidemiological study published in Nature Aging (2021) identified sildenafil as a promising candidate to reduce Alzheimer’s disease risk.[11] Analysis of health insurance records from about 7 million people revealed a 69% lower likelihood of receiving an AD diagnosis over six years among sildenafil users compared to non-users, even after adjusting for confounding variables.[11] Another observational study similarly found that older men on PDE5 inhibitors had a 25–32% reduced incidence of dementia over three years.[7]

Although these data are associative, they align with the hypothesis that improving cerebral hemodynamics and metabolic support may slow neurodegenerative processes.

3.2 Experimental and Clinical Observations

Mechanistic studies on cells and animal models reinforce the potential neuroprotective role of sildenafil. In cultured neurons, sildenafil protected mitochondria from toxic β-amyloid and advanced glycation end products. In transgenic mouse models of Alzheimer’s disease, chronic sildenafil administration improved memory, increased neurotrophic factors (e.g., BDNF), reduced neuroinflammation (elevated IL-1β, IL-6, TNF-α), and decreased pathological tau phosphorylation. Notably, most animal studies demonstrate that sildenafil lowers amyloid plaque burden, likely by suppressing β-secretase via SIRT1/PGC-1α activation.[14] Early clinical trials in humans suggest physiological benefits, such as increased cerebral blood flow and oxygen utilization in AD patients following a single dose.[15] Larger randomized phase II trials are planned to assess whether sildenafil can indeed slow cognitive decline in older adults.

4.1 Advantages of Sildenafil Use

Improvement in Sexual Function and Quality of Life

Sildenafil’s efficacy in treating erectile dysfunction in older men is well-documented, even in challenging cases such as those with diabetes.[16] Clinical trials confirm its benefit in achieving and maintaining erections in men over 65–70 years of age, leading to enhanced emotional well-being and overall life satisfaction. Sexual health is a key factor influencing mental health and relationship quality, making ED treatment a significant contributor to an improved quality of life.

4.2 Risks and Side Effects

Common Adverse Reactions

Sildenafil is generally well-tolerated,[18] but like all medications, it can cause side effects. Common issues include headache, facial flushing, dizziness, nasal congestion, and dyspepsia.[19] Some patients experience transient changes in color vision (“blue-tinged vision”) or blurred vision due to PDE6 inhibition in the retina.[20] These side effects tend to be dose-dependent, typically mild to moderate, and short-lived.