Ageotypes: When age is no longer just one number
“Which is aging more, your liver or your kidney?” might sound like a strange question to most of us, however, a recent study by Stanford Diabetes Research Center (SDRC) member and Stanford Ascherman Professor and Chair, Department of Genetics, Dr. Michael Snyder and his colleagues found that your liver could indeed age differently than your kidney.
We know that people age differently from each other. Some sixty-year-olds can run marathons while others develop diabetes. A forty-year-old might have a strong heart but a weak liver. Individual aging parameters such as cholesterol levels or glycosylated hemoglobin are useful clinical indicators but do not explain why aging is so different between people, and even within the same person over time.
“Global monitoring of molecular profiles in the same person has not been performed previously” note the authors, explaining why we don’t have a comprehensive understanding of how different pathways change in a person as they age. Dr. Snyder’s group conducted the first in-depth global analysis of over 100 molecular markers in prediabetic and healthy people from 29-75 years of age over the course of 2-3 years. The study revealed distinct aging patterns or ‘ageotypes’ within 4 biological pathways: immune, metabolic, liver and kidney function.
“We found that people age along different pathways and at different rates, something that the aging field is just beginning to appreciate”, says Dr. Wenyu Zhou, co-first author of the paper. For example, the researchers identified individuals with an immune ageotype who had an increase in immunity-related molecules with age, indicative of an aging immune system. However, they also identified people who showed the reverse immune-response trend with age, that is, a decrease in immunity-related molecules. “Notably, individuals showed distinct and sometimes opposite patterns of expression in molecules and pathways” say the authors, emphasizing the importance of a personalized approach towards assessing how people age.
Dr. Snyder’s team was especially interested in aging differences between healthy insulin sensitive (IS) and prediabetic insulin resistant (IR) people who are unable to process blood sugar efficiently. As expected, IR individuals did age differently from IS individuals – the researchers found 10 molecules that showed significantly different patterns between the IS and IR groups. Of note, many of these molecules represent an immune ageotype, “suggesting”, the authors wrote, “that individuals with IR may experience increased inflammation with age more rapidly than individuals with IS”.
The most exciting aspect of personalized medicine is the potential to improve health by targeting traits unique to the individual. The authors found that in at least a subset of participants, behavioral changes influenced their ageotype. For instance, 4 individuals who had made positive lifestyle changes to their diet or exercise regimens showed lowered glycosylated hemoglobin levels reflecting improved glucose metabolism. Dr. Zhou notes, “Knowing how each individual ages will help devise targeted and personalized interventions to battle age-related diseases”. In this context, the researchers have already filed for a provisional patent titled “Actionable diagnosis of personal aging”.
The work was a massive undertaking in terms of sample collection and analysis with more than 18 million data points generated from 106 patients via multiomics assays to track proteins, microbes, immune molecules, RNA transcripts and standard clinical markers of aging. The authors acknowledge the contributions, funding, bioinformatics and data analysis support from core facilities within Stanford including the Diabetes Genomics and Analysis Core of the SDRC, and the Stanford Center for Genomics and Personalized Medicine run by Dr. Ramesh Nair. Other Stanford co-authors include co-first author Dr. Sara Ahadi, Dr. Sophia Miryam Schüssler-Fiorenza Rose, Dr. M. Reza Sailani, Dr. Kévin Contrepois, Monica Avina, Melanie Ashland and Professor Anne Brunet.
By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.