Daily Tadalafil: Reduces All Mortality Risk In Men - A Paradigm Shift in Longevity Medicine

By Travis Smith, DO

As physicians working in precision aging and longevity medicine, we’re constantly seeking evidence-based interventions that can meaningfully impact healthspan and lifespan. Recent landmark research from major academic institutions has revealed something remarkable: daily low-dose tadalafil may be one of the most underutilized longevity interventions available today.

The Numbers Are Staggering

A comprehensive study published in The Journal of Sexual Medicine analyzed data from over 29,000 men and found that tadalafil exposure was associated with a 44% reduction in all-cause mortality compared to men not using PDE-5 inhibitors. Let me repeat that: a 44% reduction in death from any cause.

The cardiovascular benefits were equally impressive:

- 19% reduction in major adverse cardiovascular events (MACE)

- 45% reduction in cardiovascular-related mortality

- 31% reduction in coronary revascularization procedures

- 45% reduction in unstable angina

- Dose-dependent protection, with the highest quartile of exposure showing a 60% reduction in MACE

Even more recently, a 2024 study in The American Journal of Medicine analyzing data from 50 million U.S. men confirmed these findings, demonstrating that tadalafil use was associated with:

- 34% reduction in all-cause mortality

- 27% reduction in myocardial infarction

- 34% reduction in stroke

- 21% reduction in venous thromboembolism

- 32% reduction in dementia risk

Importantly, tadalafil showed superior outcomes compared to sildenafil across all measured endpoints.

Beyond Erectile Dysfunction: Understanding the Mechanisms

While tadalafil (Cialis) is FDA-approved for erectile dysfunction and benign prostatic hyperplasia, its cardiovascular and longevity benefits extend far beyond these indications. The key lies in understanding how PDE-5 inhibition affects vascular health at the cellular level.

The NO/cGMP Pathway

Tadalafil works by inhibiting phosphodiesterase type 5 (PDE-5), an enzyme that breaks down cyclic guanosine monophosphate (cGMP). When cGMP levels increase, several critical physiological processes are enhanced:

Endothelial Function Restoration: Multiple studies have demonstrated that chronic tadalafil administration significantly improves flow-mediated dilation (FMD), a gold-standard measure of endothelial health. In one randomized controlled trial, FMD improved from 4.2% to 9.3% after just four weeks of therapy—and these benefits persisted for at least two weeks after discontinuation.

Nitric Oxide Bioavailability: Tadalafil amplifies endothelial nitric oxide (NO) signaling, promoting vasodilation and improving blood flow throughout the entire vascular tree—not just in the penis. This is crucial because endothelial dysfunction is the earliest detectable change in the development of atherosclerosis and cardiovascular disease.

Anti-inflammatory and Anti-thrombotic Effects: Research shows that tadalafil reduces markers of inflammation (including endothelin-1, VCAM, and CRP) and improves the balance between prostacyclin and thromboxane A2, creating a more favorable anti-thrombotic environment.

Endothelial Progenitor Cell Mobilization: Chronic tadalafil treatment has been shown to increase circulating endothelial progenitor cells, which play a vital role in vascular repair and regeneration.

The Long Half-Life Advantage

One of tadalafil’s unique features is its extended half-life: 17.5 hours in healthy adults and up to 21.6 hours in older individuals. This stands in stark contrast to sildenafil’s approximate 4-hour half-life. This pharmacokinetic profile means:

- Daily 5mg dosing provides 24-hour vascular protection

- More consistent endothelial support throughout the day and night

- Better adherence due to once-daily dosing

- Sustained improvements in morning erections, which may contribute to penile tissue oxygenation and health

The Dose-Response Relationship

The research reveals a clear dose-response relationship: men in the highest quartile of tadalafil exposure had the lowest rates of adverse cardiovascular events. This suggests that regular, consistent dosing—rather than sporadic on-demand use—is key to achieving maximal cardiovascular and longevity benefits.

The standard daily dose of 5mg tadalafil appears to be the optimal balance of efficacy and safety for most patients, though some may benefit from titration to 10mg or 20mg based on individual response and tolerability.

Who Should Consider Daily Tadalafil?

Based on the available evidence, daily low-dose tadalafil should be considered for:

- Men over 40 with cardiovascular risk factors (hypertension, dyslipidemia, diabetes, smoking, family history)

- Men with erectile dysfunction of any severity

- Men with lower urinary tract symptoms from benign prostatic hyperplasia

- Men with documented endothelial dysfunction

- Men interested in evidence-based longevity interventions

Important Note: The studies showing mortality benefits primarily included men with cardiovascular risk factors. While the mechanisms suggest potential benefits for healthy individuals, more research is needed in lower-risk populations.

Safety Considerations

Tadalafil has an excellent safety profile. The most common side effects are mild and include:

- Headache

- Flushing

- Nasal congestion

- Indigestion

- Back pain

Critical Contraindications:

- Concurrent nitrate use (nitroglycerin, isosorbide, etc.) due to risk of severe hypotension

- Severe cardiovascular disease with recent MI or stroke

- Severe hepatic impairment

- Hypotension or uncontrolled hypertension

Regular monitoring is appropriate, particularly in patients with underlying cardiovascular conditions or those on multiple medications.

A Practical Approach in My Practice

At Bio Precision Aging, we’re increasingly incorporating daily tadalafil into our comprehensive longevity protocols. Here’s our typical approach:

1. Baseline Assessment: Comprehensive cardiovascular evaluation including lipid panel, inflammatory markers, metabolic panel, and assessment of cardiovascular risk factors

2. Initiation: Start with tadalafil 5mg daily (or 10mg every other day as an alternative). Outside of insurance coverage, obtaining through compounding pharmacies and using coupons like Good Rx are the easiest and cheapest ways.

3. Monitoring: Follow-up at 3 months to assess tolerability, adherence, and subjective benefits; repeat vascular assessments at 6-12 months

4. Optimization: Adjust dosing based on individual response, side effects, and clinical goals

The Bigger Picture: Rethinking “Off-Label” Use

One of the challenges in longevity medicine is that many of our most promising interventions are “off-label” uses of FDA-approved medications. Tadalafil for longevity falls into this category. However, the evidence base is now substantial and growing.

When we have multiple large-scale studies showing 30-44% reductions in mortality with an inexpensive, well-tolerated daily medication, I believe we have an ethical obligation to discuss this option with appropriate patients. This isn’t experimental medicine—it’s evidence-based precision aging.

Future Directions

Several important questions remain:

Women: While current data focuses on men, PDE-5 inhibitors are sometimes used off-label in women for various conditions. Future research should explore whether similar cardiovascular and longevity benefits exist for women.

Mechanism Studies: More research is needed to fully understand which mechanisms account for the mortality benefits. Is it purely vascular? Do anti-inflammatory effects play a role? What about potential effects on mitochondrial function or cellular senescence?

Combination Therapies: How does tadalafil interact with other longevity interventions like metformin, rapamycin, or NAD+ precursors?

Optimal Duration: What is the minimum treatment duration needed to see benefits? Do benefits continue to accrue with longer-term use?

Conclusion

The evidence is clear and compelling: daily low-dose tadalafil represents a powerful, underutilized tool in our longevity medicine arsenal. With nearly 50% reductions in mortality, significant cardiovascular protection, and even cognitive benefits through reduced dementia risk, this is not just about erectile function—it’s about optimizing vascular health, the foundation of healthy aging.

As always, the decision to start any medication should be made in consultation with a physician who understands your individual health profile, risk factors, and goals. But for appropriate patients, particularly those with cardiovascular risk factors or established endothelial dysfunction, the evidence supporting daily tadalafil is now too substantial to ignore.

Disclaimer: This article is for educational purposes only and does not constitute medical advice. All treatment decisions should be made in consultation with a qualified healthcare provider. Dr. Smith has no financial relationships with manufacturers of tadalafil or any PDE-5 inhibitors.

Key References:

1. Kloner RA, et al. “The association of tadalafil exposure with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction.” Journal of Sexual Medicine, 2024. PMID: 38377018

1. Lan TY, et al. “Benefits of Tadalafil and Sildenafil on Mortality, Cardiovascular Disease, and Dementia.” American Journal of Medicine, 2024. PMID: 39532245

1. Rosano GM, et al. “Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk.” European Urology, 2005. PMID: 15661417

1. Aversa A, et al. “Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study.” International Journal of Impotence Research, 2007. PMID: 16943794

1. El-Sayed MI, Amin HA. “Mechanism of endothelial cyto-protective and thrombo-resistance effects of sildenafil, vardenafil and tadalafil in male rabbit.” Archives of Medical Science, 2015. PMID: 25861307

For more information about precision aging and evidence-based longevity, visit bioprecisionaging.com