Mortality and longevity

In health, longevity emphasizes healthspan—the years of functional, disease-free life—over mere lifespan. Extending healthspan is the primary goal, which directly lowers the risk of All-Cause Mortality (ACM), the death rate from all causes combined.

ACM risk is a statistical measure. For a group, a 40% increased risk means that group will experience 40% more deaths than a comparable group without the risk factor. For an individual, this is not a prediction but a measure of probability; it increases the statistical chance of premature death, but does not guarantee it, as personal health outcomes depend on a complex mix of genetics, environment, and multiple lifestyle factors.

Testosterone levels significantly affect longevity, as low testosterone is a well-established marker of poor health and is strongly linked to a higher risk of premature death from all causes. This increased risk stems from testosterone's crucial role in regulating metabolism, body composition, and inflammation. Deficient levels contribute to conditions like obesity, insulin resistance, and heart disease, thereby reducing longevity. Restoring testosterone in deficient men appears to mitigate this risk, potentially improving survival without increasing mortality.

Effect of low-T

Low testosterone significantly increases mortality risk: Men with testosterone below 7.4 nmol/L (213 ng/dL) have 35% higher all-cause mortality, and below 5.3 nmol/L (153 ng/dL) have increased cardiovascular death risk.
Severe testosterone deficiency dramatically increases mortality: Men with late-onset hypogonadism have 5-fold higher mortality risk, while low testosterone alone doubles death risk compared to normal levels.
Testosterone replacement therapy appears protective: Treatment reduces mortality from 20.7% to 10.3% in observational studies, with treated men showing 39% lower death risk (HR 0.61).
Combined low testosterone plus symptoms creates highest risk: Men with both low testosterone and sexual dysfunction symptoms have over 5-fold increased mortality risk compared to those with normal levels.
Diabetes amplifies testosterone-mortality relationship: Diabetic men with low testosterone have 17.2% mortality versus 9% with normal testosterone, but TRT reduces this to 8.4%.
Effect is age-dependent and dose-responsive: Mortality risk increases most sharply after age 60-80, with each 6 nmol/L testosterone increase associated with 19% lower mortality risk.

Limitations: The evidence that TRT reduces all-cause mortality (ACM) comes primarily from observational studies rather than randomized controlled trials, creating moderate-quality evidence. While observational data suggests TRT may reduce mortality by approximately 20-40% (from studies showing mortality reduction from 20.7% to 10.3% and hazard ratios around 0.61), large RCTs have indicated the true mortality benefit may be modest at 10-20%.

Endogenous Testosterone and Mortality due to All Causes, Cardiovascular Disease, and Cancer in Men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study (18040028) (2007) (Observational Study)

Men with higher testosterone levels had significantly lower risk of death from all causes, cardiovascular disease, and cancer.
Each 6 nmol/L increase in testosterone was associated with 19% lower mortality risk.
The protective effect remained strong even after adjusting for multiple health factors including BMI, blood pressure, cholesterol, smoking, and diabetes.
Low testosterone appears to be a predictive marker for men at high cardiovascular disease risk.
The study followed 11,606 men aged 40-79 for up to 10 years with 825 deaths recorded.

Late-Onset Hypogonadism and Mortality in Aging Men (24423283) (2014) (Observational Study)

Men with severe late-onset hypogonadism had a 5-fold higher risk of all-cause mortality compared to men without the condition.
Low testosterone alone (below 8 nmol/L) doubled mortality risk, while sexual symptoms alone tripled the risk.
The combination of low testosterone plus sexual symptoms created the highest mortality risk.
Cardiovascular mortality showed similar patterns to all-cause mortality.
The study tracked 2,599 European men aged 40-79 for a median of 4.3 years, during which 147 deaths occurred.

Endogenous Testosterone and Mortality in Men: A Systematic Review and Meta-Analysis (21816776) (2011) (Meta-Analysis)

This meta-analysis of 12 studies with 16,184 men showed that low testosterone was associated with a 35% higher risk of all-cause mortality.
Cardiovascular mortality risk increased by 25% in men with low testosterone.
The analysis suggested that low testosterone may be a marker of overall poor health rather than a direct cause of death.
Effects were strongest in older men, those with lower baseline testosterone, and in studies with shorter follow-up periods.

Testosterone Deficiency is Associated with Increased Risk of Mortality and Testosterone Replacement Improves Survival in Men with Type 2 Diabetes (23999642) (2013) (Observational Study)

Men with diabetes and low testosterone had a 17.2% mortality rate versus 9% in those with normal testosterone over 6 years.
Testosterone replacement therapy reduced mortality to 8.4% compared to 19.2% in untreated low-testosterone men.
Low testosterone doubled the risk of death in diabetic men even after adjusting for other health factors.
Treatment appeared to restore survival rates to levels similar to men who had normal testosterone from the start.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality (38739921) (2024) (Meta-Analysis)

This large meta-analysis of 11 studies with 24,109 men used highly accurate mass spectrometry testing.
Men with testosterone below 7.4 nmol/L (213 ng/dL) had a significantly higher risk of all-cause mortality.
A testosterone level below 5.3 nmol/L (153 ng/dL) was linked to an increased risk of cardiovascular death.
The results remained significant after adjusting for age, BMI, lifestyle factors, and other cardiovascular risk factors.

A Meta-Analysis of Randomized Controlled Trials on Testosterone Replacement Therapy and Cardiovascular Outcomes (37797887) (2024) (RCT Meta-Analysis)

This meta-analysis of 26 randomized controlled trials (RCTs) with 10,941 men found no increased mortality risk with testosterone treatment.
There were no significant differences in cardiovascular deaths, heart attacks, strokes, or other major cardiovascular events between treatment and placebo groups.
The results provide high-quality evidence reassuring that testosterone replacement therapy does not worsen cardiovascular outcomes.

Adverse Cardiovascular Events and Mortality in Men During Testosterone Treatment (35711614) (2022) (RCT Meta-Analysis)

This meta-analysis of 17 randomized trials with 3,431 men used individual participant data for high accuracy.
Fewer deaths occurred with testosterone treatment (0.4%) compared to placebo (0.8%).
The study found no significant increase in cardiovascular or cerebrovascular events with testosterone therapy.
This provides strong evidence from clinical trials that testosterone replacement does not increase mortality or cardiovascular risk.

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