Glycan Biology and Early Disease Prediction: The Next Chapter

This past October, at the Global Longevity Summit in Geneva, Switzerland, I shared a panel on the topic of “biological clocks” with Gordon Lauc, glycan biology pioneer and the developer of the GlycanAge biological clock. I came back to New York convinced that a new frontier in longevity medicine was opening up, using glycan diagnostics not only to predict biological age, similar to the way that the more familiar epigenetic clocks do, but also to predict the risk of specific chronic diseases years before first symptoms might reveal themselves to conventional medical testing.

First, a little background. The concept of biological age has always been the cornerstone of my longevity practice. Unlike chronological age, it’s mostly a matter of measurable function -- how the different systems of your body test out over time. In recent years, I, like many in the field, have integrated epigenetic clocks into the mix. From a single blood draw, these clocks analyze the epigenome, specifically the pattern of chemical markers that determine when and which genes get expressed and, consequently, which proteins get made in order to run the body. While our genes are fixed at conception, our epigenetics are in flux throughout our lifetime, responding, in healthy or unhealthy ways, to our lifestyle and environment.

Epigenetics marks a revolution in biology. But it’s been followed by another one, glycan biology. For the past thirty or so years or so, researchers have been figuring out how proteins, once they’re created, behave, depending on which and how many glycans -- complex sugars -- attach to their structures. (Leave it to nature to make use of something as seemingly ordinary as sugars to perform this sophisticated function.) Similar to the way lifestyle affects the methylation patterns of epigenetic markers, it also acts on how glycans attach to proteins, a process called glycosylation. In simplest terms, the more glycans that attach to a protein, the better that protein does its job, interacting with neighboring cells, and the less prone to generating inflammation. (Seen with an electron microscope, a protein with lots of glycans looks like a bushy tree, with few glycans, more like Charlie Brown’s Christmas tree.)

In a post last year, I explained how Gordon Lauc, my co-panelist in Geneva, developed the technology to analyze the glycan structure of a single protein – immunoglobulin G (IgG), the most common antibody in the immune system. His GlycanAge panel, now used in longevity practices globally, tells us how “old,” in other words how inflammatory, a patient’s immune system is. To a large degree, as the immune system ages, so does the rest of us – hence “GlycanAge.”

(The GlycanAge panel offers a three-month-long window into IgG glycosylation, about the same window that the standard hemoglobin A1c metabolic-health test provides for “glycation,” the random, harmful attachment of the simple sugar glucose onto proteins, confusingly, a totally different process.)

In Geneva, Lauc described the next chapter in the unfolding glycan story. In a series of academic papers, some published as recently as a few months ago, he and his colleagues mapped the GlycanAge glycosylation patterns they’d identified onto huge patient “bio-banks” that include blood samples and long-term medical histories, and looked for the correlations that popped. What they found was that certain patterns (not the ones used to calculate glycan “age” but that also turn up on the GlycanAge panel) could be used to predict which people are more, or less, at risk for developing particular diseases and outcomes: coronary artery disease, cardiovascular events, hypertension, afib, type 2 diabetes.

I should say that the FDA (as well as the health insurance industry) has not yet approved these panels as validated disease risk markers. That will probably have to wait until the next generation of studies demonstrates outcomes, by tracking groups of people who have favorably changed their glycosylation scores in order to determine if, on average, over time, they experience better health outcomes than a control group. If, as I expect, these studies pan out, then glycan scores will join, for instance, cholesterol and blood pressure not only as markers for heart disease risk but as therapeutic targets as well – improve your score, improve your prospects for living a longer and healthier life. This contrasts to the epigenetic clocks which remain something of a “black box.” These clocks analyze areas of the genome that usually lie outside of the genes themselves so we often don’t know what effect these measurable epigenetic changes are having on the expression of genes that actually drive the cellular aging process.

Already, the consensus in the longevity field is that the glycan cardiovascular disease score is at least as accurate a predictor of future cardiovascular events as, say, the Framingham risk calculator, which crunches a wide range of health data – cholesterol, blood pressure, blood sugar, etc. – to come up with an individual’s risk score. Keep in mind, the glycan data is revealing only one aspect of the heart disease process – inflammation as mediated by IgG – which tells you that heart disease must truly be considered a chronic inflammatory condition.

It’s perhaps the inflammation piece of the puzzle that explains how it is that I’ve run high LDL numbers for most of my adult life and yet advanced imaging studies tell me I have no visible signs of coronary plaque accumulation. The same is true for many of my patients. That’s because we have low levels of systemic inflammation, as indicated by the glycan diagnostic data as well as other more conventional measures. LDL loads the “gun” of heart disease, inflammation pulls the trigger.

Certainly, a relatively healthy lifestyle is a factor here – exercise especially. But the biggest factor is the youthful sex hormone levels that hormone replacement therapy provides me and my patients – estrogen for women, testosterone for men. Estrogen helps regulate IgG glycosylation so women on HRT receive boosted immunity and inflammation suppression directly, men indirectly, when some of the supplemental testosterone is converted into estrogen. In my view, these immunity/anti-inflammation benefits are some of the most potent – and underappreciated – benefits of HRT. In my practice, I’ve seen 60-year-old women and men drop their GlycanAge by forty years after going on hormone therapy. That doesn’t mean they’ve become twenty, but it does mean that the patterns of glycans on their IgG antibodies have been modified back to the way they were when they were twenty.

I’ve collaborated with Gordon Lauc on different projects in the past so I was hardly a stranger to glycans before the Geneva panel. But I returned with an even stronger feeling that glycan-based diagnostics gives us a clinically meaningful way to penetrate the reversible biology of human aging. By capturing cellular aging at the DNA level, the epigenetic clocks give us a good approximation of biological age. But unravelling the “glycome” can help us slow that aging process, by illuminating the strategies that we might take – specific lifestyle upgrades, hormonal therapies – to reduce inflammation and to reach, some day, our healthiest old age.

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Yazdani A, Hoshi R, Ammar M, et al. Statin effects on immunoglobulin-G glycomic architecture and the link to cardiovascular disease. Res Sq [Preprint]. 2025 Mar 3:rs.3.rs-6112380. doi: 10.21203/rs.3.rs-6112380/v1. PMID: 40092445; PMCID: PMC11908345.

Hoshi RA, Plavša B, et al.. N-Glycosylation Profiles of Immunoglobulin G and Future Cardiovascular Events. Circ Res. 2024 Mar;134(5):e3-e14. doi: 10.1161/CIRCRESAHA.123.323623. Epub 2024 Feb 13. PMID: 38348651; PMCID: PMC10923145.

Plavša B, Szavits-Nossan J, et al. The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation. Biomolecules. 2023 Mar 28;13(4):605. doi: 10.3390/biom13040605. PMID: 37189353; PMCID: PMC10135591.