Inflammation increases with age, but we still don’t understand why it occurs, Lauck says. Glycan analysis may shed light on this. He studies how these branched, structurally diverse sugar molecules differ between individuals and how they influence disease and aging. Glycans coat mammalian cells and bind to proteins such as immunoglobulin G (IgG). His company performs large-scale glycan analysis, and the proceeds help fund his grants and his team’s glycan research. He and his team are working on developing glycan clocks for use in diagnostics and basic research, and work is progressing slowly. Glycans are complex molecules, and “the main problem with glycans is that we need more people in this field,” he says.
One aging signal arises from changes in the structure of glycans covalently attached to IgG. In conditions associated with low-grade systemic inflammation, such as cardiovascular disease, levels of galactose and sialic acid in IgG glycans are reduced, and this change is associated with accelerated aging, he says. . Aggregating such changes is a kind of clock, and his is one of many that aging researchers can refer to to address many fundamental unanswered questions about aging.
Like many older researchers, he appreciates the epigenetic clock widely used at the Horvath Institute. Lauc was part of the projectFour Dr. Horvath used several methods, including this epigenetic clock, to measure the results of experiments in which rats showed significant age reversals. “But I’m always very cautious,” he says of this finding, which still needs confirmation by others.
The researchers administered a fraction containing exosomes from the plasma of young adult pigs to rats. The rats’ livers, hearts, and brains showed improved function. Experiments that mix the blood of old and young mice are not new, but what was new to Lauck was the way the clock could be used to assess rejuvenation in rats.
The team studied the animals’ physiology, conducted cognitive tests, and performed histological and biochemical tests. They also profiled changes in IgG glycosylation. The blood, heart and liver of these rats had halved their previously measured epigenetic age.
Horvath doesn’t mind being called the “father of epigenetic clocks.” He developed his first paper in 2011, but that paper “was largely ignored,” he says.Things changed when he followed up with multi-tissue testing.Five This method was deemed to provide an important biomarker of aging. The concept that methylation reflects the activity of a cell’s epigenetic maintenance system has gained attention. The epigenetic clock is a multivariate age estimator based on methylation measurements such as the Mammalian Methylation Consortium array. The clock utilizes a public dataset of millions of methylation sites within the human genome. A subset of methylated sites is used to build a clock with regression models and machine learning. Since then, Horvath has developed clocks that are specific to different species, clocks that span tissues, and even clocks that are common to mammals.6. Species and different tissues within a species exhibit patterns of epigenetic changes.
Cohort studies have shown that this epigenetic clock can predict both lifespan and healthspan because it accounts for the difference between methylation-based age and chronological age, Horvath says. His second generation epigenetic clock is called his GrimAge, named after the Grim Reaper. In his view, this is a strong molecular predictor of mortality risk.
When he arrived at UCLA, like many people at the time, “I had all sorts of prejudices against methylation,” he says. His colleague Eric Villane proposed evaluating methylation differences between Horvath’s gay twin brother and his straight Horvath. “We found zero. There was nothing,” Horvath said, finding no relationship between methylation levels and sexual orientation. “Then, of course, we looked at the effects of aging, and the rest is history,” he says.
In 2023, he published a pan-mammalian universal clock. “I’m very happy that we were able to do that,” Horvath said. The next step might be to construct a clock for all vertebrates with cytosine methylation. “For me, this challenge is so difficult that I’m not going to tackle it,” he says, but he hopes the next generation of older researchers will take on the challenge.
Gorbunova and Horvath built an epigenetic clock for naked mole rats. She is familiar with pan-mammalian clocks, which she also likes. In her experience, it’s not as accurate as species-specific. More generally, she says, the epigenetic clock doesn’t tell us when it’s time to write a will. However, the clock can help predict healthspan in large-scale cohort analyses.
“We’re very interested in developing more accurate clocks,” she says. With the tools Horvath has, building such a clock is fairly easy. “The only limitation is sample availability,” she says. At least 100 samples are required to train a clock for an individual species.
Scientists are faced with a wide choice of clocks7 It exceeds that of the Horvath Institute. “Aging watches are great, but they’re all different, and you need to know what each one is measuring to really take advantage of it,” he says. “Being plural has its pros and cons,” Horvath says. His two papers on a similar question may have used different clocks, making it difficult to compare the results.
In his paper, Horvath also includes evaluations of other clocks when explaining his selection of the second-generation epigenetic clock, GrimAge, as the best predictor of mortality risk in blood samples. He sees other study authors evaluating the watches as well. One danger, Horvath says, is that labs may try several experiments and “only report on the ones that yield the expected results.” Not only is this an unsatisfactory practice, but it can be detrimental to the field and damage the watch’s reputation more generally.
After 30 years of debate over whether aging is “wear and tear” or definitive, “we now know that, at least in mammals, it is definitive,” Horvath said. In fact, there is only a weak relationship between epigenetic changes and gene products on the one hand, and changes in proteins and metabolomic data on the other. Because biology occurs at the protein level, it is unclear what exact effects methylation has. “And to this day, we struggle with that question.”
