Longevity medicine has come of age in the past 5 years with the evidence mounting that certain drug therapies look to be able to postpone or protect against multiple chronic diseases, quite possibly by pushing back against the underlying biological processes of aging itself. Metformin, the near-ubiquitous diabetes drug, and rapamycin, prescribed to suppress the immune system in organ transplant patients, are the two drugs that have garnered the most attention. But for my money, hormone therapy is still the most potent “anti-aging” therapy going, especially for women. (More recent HRT research has demonstrated impressive decreases in the rates of cardiovascular disease, the leading killer of women.)
Now we have a new study that adds to this body of evidence, a head-to-head comparison between men receiving supplemental testosterone versus those taking metformin. While the benefits of increasing testosterone levels are well-known – more energy, an anabolic muscle-building or preserving boost, enhanced libido – it’s rarely if ever been touted as a longevity drug. In fact, only recently has it emerged from the shadow of misplaced fears that it could shorten lifespan, by increasing cancer or heart disease risk. (HRT had to overcome a similar prejudice.) But in the study, published this fall in GeroScience, testosterone outperformed metformin in a way that suggests a significant longevity benefit. Exactly how it did so is a fascinating story that requires some context, as you may discern from the study title: “Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome.”
That’s a lot to unpack so let’s begin at the beginning. One of the biggest recent breakthroughs, not just in longevity research but in biology period, has been the ongoing unraveling of the role of glycans in maintaining and regulating life as we know it, from plants to humans. What are glycans? They are oligosaccharides (small groups of sugars), structurally more complex than glucose, the simple sugar that is the building block of carbohydrate. Directed by specific enzymes, these glycans attach to proteins (and lipids) over the course of an organism’s lifetime, modifying both their shape and their function. How they do this is, in part, a response to the environment the organism (let’s say you) finds itself in. A healthy diet, plenty of exercise, no smoking, no excessive alcohol consumption – all of that contributes to “glycosylation” patterns that promote health and, we can assume, longevity; the opposite lifestyle habits do the opposite.
That may have a familiar ring to it, as I’ll explain.
We all share the same basic collection of genes – the human genome. And we each have our own individual genetic “fingerprint,” a particular collection of mutations (technically, our SNPs or single nucleotide polymorphisms) that make us a little bit different than our neighbor. But there’s another level of individualization that goes beyond the genes, fixed at conception, and that’s our epigenetics, the sum of the chemical messengers that determine which genes get turned on and when, in order to make specific proteins. And our epigenome is influenced by our lifestyle: exercise, diet and all the rest. What more recent research has revealed is yet another level of individuation – our glycome. Those lifestyle-sensitive glycosylation patterns influence how a particular protein goes about doing its job in the body. (Glycosylation is often wrongly confused with “glycation,” a random, harmful process whereby glucose attaches to protein, something that’s captured by the standard blood sugar level test, hemoglobin A1C.)
The number of variations in protein behavior that the glycome makes possible is mind-boggling. But the Croatian glycobiologist Gordan Lauc came up with a kind of shortcut to derive actionable information from an individual’s glycome, by analyzing the glycosylation patterns of a single protein, IgG (Immunoglobulin G), the most common antibody of the human immune system. These patterns tell us whether IgG antibodies are behaving in a pro-inflammatory or anti-inflammatory fashion, information that Lauc’s company GlycanAge uses to generate, you guessed it, an individual’s GlycanAge. The number is a handy read-out for how that individual’s immune system is aging. That, in turn, gives us a fair idea of their overall rate of aging, chronic inflammation being implicated in most or all of the most common diseases of aging, to such a degree that some researchers use the term “inflammaging” as a shorthand for the aging process in general.
In Lauc’s new paper, which I was a co-author on, the research subjects – obese men with low testosterone levels – who received supplemental testosterone saw a bigger drop in their GlycanAge than those who took metformin over the year-long study period. Those results were corroborated in a real-world way by a one-point-in-time analysis of my (non-obese) Raffaele Medical practice patients who were either on testosterone or metformin. Both the longitudinal randomized control trial and the cross-sectional analysis confirm the results of a previous study, namely that glycosylation patterns are strongly affected by our sex hormones, specifically estrogen, not only in women, but also in men. (Some amount of testosterone is converted in the male body to estrogen.)
The results of the study were gratifying. I believe GlycanAge is valuable not only as a marker of aging but as a means to better understand glycosylation as a driver of aging, which should allow us to better predict disease risk and to develop disease-specific drug therapies. The results are also a further confirmation of my belief that hormone therapies, for women and for men, are currently the most powerful anti-aging medications in our longevity medicine toolbox.
José Carlos Fernández-García and Gordan Lauc, et al. Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome. GeroScience. 2024 Oct 4. doi: 10.1007/s11357-024-01349-z.
Gordan Luac, et al. Glycans Are a Novel Biomarker of Chronological and Biological Ages. J Gerontol A Biol Sci Med Sci. 2013 Dec 10;69(7):779-789. doi: 10.1093/Gerona/git190
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