Is Your Testosterone High Enough to Thrive?

Twenty-five years ago, when I began my longevity medicine practice, I considered testosterone therapy the single most powerful tool in my toolbox to enhance my male patients’ health and well-being. I still do. The research amassed over the past 10 years has confirmed my clinical experience that optimizing men’s testosterone to the levels they may have enjoyed in their twenties or thirties can meaningfully resist the gravitational forces of male aging, the not-so-inevitable declines in body composition, libido, energy and mood that so often characterize men’s middle and later years. 

Mainstream endocrinologists  are beginning, but only beginning, to catch up. We still have a very different take on if and how to treat  low-normal testosterone patients, above the pathologically low or “hypogonadal” range. In my view, the endocrinologists and mainstream medical community fail to see the broader benefit of testosterone therapy because they’re still wedded to classic Western medical “binary” thinking – i.e., either you have a specific condition or you don’t. Therefore, a patient with a testosterone of 290 ng/dl may be treated – it’s an “abnormally” low value -- and one with 310 ng/dl probably should not be – it’s a “normal” value. But there’s no meaningful biological difference between those two numbers; the cut-off is relatively arbitrary. 

By the time men hit their 40s, their free testosterone levels typically decline by about 1-2% a year. The decline is often subtle and gradual. Early signs – fatigue, low mood, creeping weight gain – can appear long before levels dip below some arbitrary threshold. Shouldn’t we arrest the hormonal slide when the patient is still relatively healthy, before age-related conditions like sarcopenia, osteoporosis, and metabolic syndrome present, before the window begins to close on impactfully increasing the number of disease-free years he can expect to live?

The first barrier to the broader use of testosterone therapy were the questions about its long-term safety. Some feared that that supplemental hormone might increase the risk of prostate cancer, mostly because androgen-deprivation therapy has been used to treat the disease. Additionally, a few small, poorly controlled studies had suggested the possibility of an increased risk of cardiovascular events although others had actually shown benefit. The concern about heart attack and stroke was enough for the FDA in 2014 to slap a “black box” warning on testosterone products.

More recent and better-done research has by now convinced most in the field those early fears were overblown. Multiple studies, most prominently a 2016 study published in Urologic Clinics of North America, have shown no increased prostate cancer risk. While no large randomized controlled trial exists—likely due to lack of pharmaceutical company funding—the weight of observational evidence is reassuring.

As for cardiovascular risk, the best evidence we have is from the 2023 TRAVERSE trial, published two years ago in the New England Journal of Medicine. Over a period of several years, a small army of leading endocrinologists tracked nearly 5,200 men, men between the ages of 45 to 80, all with low testosterone levels, all with some degree of cardiovascular disease, half receiving the supplemental testosterone, half not. Their conclusion? With regard to cardiovascular events, receiving the supplemental testosterone was “non-inferior” to placebo, meaning, no more dangerous than doing nothing. 

While TRAVERSE had its limitations—including high dropout rates and only modest testosterone increases — it has allayed most of the cardiovascular concerns, especially when considered alongside a newer study that came out this past March. That study -- “Association between Low Serum Testosterone Levels and All-cause Mortality in Patients With Cardiovascular Disease: A Study Based on the NHANES Database” – tracked close to 700 older men in the government’s health records database, all with cardiovascular disease, for an average of 4 ½ years. The men who fell in the “hypogonadal” category – that is, their testosterone levels were 300 (ng/dL) or less – were almost 1.5 times more likely to die than men with normal levels. (Women were also included in the study but no association was found between testosterone and mortality.)

True, the NHANES paper doesn’t establish causality. The factors that drive

cardiovascular disease also push down testosterone. But everything we know about the major role that testosterone plays in most every organ system suggests a two-way relationship – low testosterone levels and cardiovascular risk factors like obesity and high blood sugar almost certainly act upon each other.

When we’ve got a handle of the (modest) risks associated with testosterone therapy and a sense of its potential benefit, then we need to think about how and when to use it. Mainstream endocrinologists and I would both treat the patient with a testosterone level of 300 or less – we’re talking about 1 in 5 men in their sixties and likely a majority of men with cardiovascular disease. But the endocrinologist would usually first want to hear about symptom complaints before prescribing whereas I assume there are symptoms whether the patient writes it off to “normal aging” or not.

I’ve come to see testosterone not just as a way to fix what's failing, but as a tool to shift the trajectory before decline sets in. Here’s some of the research that shaped that view. 

Muscle Preservation and Physical Function

Age-related muscle loss (sarcopenia) accelerates after age 50. Notable then that in a three-year study of testosterone supplementation published in the Journal of Clinical Endocrinology & Metabolism, older men with low-normal levels had significant increases in lean mass and grip strength. It’s that preservation of muscle mass and strength that is crucial for maintaining mobility, preventing falls, and sustaining an independent life in the older years. I see this in my practice all the time. 

Metabolic Health

Testosterone plays a key role in glucose metabolism and insulin sensitivity. Multiple studies, including a 2016 study in Diabetes Care, show that low testosterone predicts development of type 2 diabetes, while testosterone optimization therapy can improve insulin sensitivity. Often, the positive metabolic effect of the extra testosterone is indirect. The patient feels more energetic and is more likely to exercise regularly, and recover faster. The result: more muscle and an easier time managing weight. 

Cognitive and Mental Health

The emerging evidence suggests testosterone supports cognitive function and mental health. A 2019 meta-analysis published in JAMA Psychiatry found associations between higher testosterone levels and reduced depressive symptoms in aging men. There are lots of testosterone receptors in the brain regions involved in mood regulation and executive function, a plausible biological mechanism.

We’ve just ticked off a lot of boxes for the aging male: muscle, metabolism and mood. But there’s another important one to add.  

Novel Biomarkers: The GlycanAge Revolution

GlycanAge, a new biomarker of aging, is a measure of epigenetic changes in the immune system (or more precisely, of Immunoglobulin G glycosylation patterns). It reflects both chronological age and systemic inflammation.  Recent research by Vinicki et al. demonstrates that lower testosterone correlates with older GlycanAge while hormone therapy can reduce GlycanAge, sometimes dramatically, predominantly through testosterone’s conversion to estradiol. To my mind, this is an exciting and direct connection between testosterone and longevity. 

A New Treatment Paradigm

What I am proposing is a more proactive approach to hormone therapy, tailored to the individual – his personal response to the therapy, his health status, his biomarkers, his therapeutic goals. It doesn’t mean that increasing hormone levels with injections or gels is always the right approach. For instance, for an overweight patient, especially a younger patient whose testes may be capable of producing a good amount of testosterone, my first-line therapy might be a GLP-1 agonist drug – visceral fat goes down, the pituitary signal to the testes to produce testosterone goes up. What it does mean is monitoring testosterone earlier—ideally in a man’s 40s or as soon as symptoms appear. We should aim for optimal levels—typically between 500 and 900 ng/dL—to support energy, mood, and long-term vitality.

This kind of approach isn’t new—it’s how we already manage things like cholesterol and blood pressure. We intervene early to hit targets that are known to correlate with better outcomes. Testosterone should be no different. When properly monitored, testosterone optimization appears safe and offers benefits far beyond symptom relief—potentially slowing biological aging itself. The question shouldn't be "Is your testosterone low enough to treat?" but rather "Is your testosterone high enough to thrive?"

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Davidson E, Morgentaler A. Testosterone Therapy and Prostate Cancer. Urol Clin North Am. 2016;43(2):209-216. doi:10.1016/j.ucl.2016.01.007

Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. doi:10.1056/NEJMoa2215025

Jiang R, Wang Y. Association between Low Serum Testosterone Levels and All-cause Mortality in Patients With Cardiovascular Disease: A Study Based on the NHANES Database. Cardiovasc Toxicol. 2025;25(4):604-613. doi:10.1007/s12012-025-09973-7

Storer TW, Basaria S, Traustadottir T, et al. Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men. J Clin Endocrinol Metab. 2017;102(2):583-593. doi:10.1210/jc.2016-2771

Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. 2016;39(1):82-91. doi:10.2337/dc15-1518

Walther A, Breidenstein J, Miller R. Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2019;76(1):31-40. doi:10.1001/jamapsychiatry.2018.2734

Krištić J, Vučković F, Menni C, et al. Glycans Are a Novel Biomarker of Chronological and Biological Ages. J Gerontol A Biol Sci Med Sci. 2014;69(7):779-789. doi:10.1093/gerona/glt190

Vinicki M, Pribić T, Vučković F, et al. Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome. GeroScience. Published online October 4, 2024. doi:10.1007/s11357-024-01349-z