INFORM October 2025

inform October 2025, Vol. 36 (9) • 11

contribute to poor joint health. “One of our problems is, when we have really bad diets, we age our joints and other parts of our body faster,” Guilak said. Fat-1 gene therapy successfully mitigated cellular aging. Mice fed a high-fat diet and given fat-1 gene therapy showed reduced levels of cellular senescence markers. Converting omega-6 fatty acids to omega-3 fatty acids in mice via gene therapy, slowed down that accelerated aging process, Guilak said. Obesity contributes to OA progression and is a signifi cant, preventable risk factor. However, for many years people believed that the connection between obesity and OA was due to weight-related increased loading and eventual breakdown of the joints. Guilak said that people dismissed OA develop ment in obese people as wear and tear on overloaded joints. Researchers have revealed a more complex relationship, how ever. Systemic, persistent inflammation has a significant role in OA development. “It turns out a major component is the inflammatory and metabolic environment that occurs with obesity,” said Guilak. “They have this low-grade, chronic, systemic inflammation.” Circulating pro-inflammatory mediators, such as cytokines IL-1β, TNF-α, and IL-6, impact OA (https://tinyurl.com/923781). Guilak said fat produces many of these pro-inflammatory many researchers to conclude that the omega-6/omega-3 ratio does not convey the nuanced role of individual fatty acids. The ratio may also be unhelpful when determin ing the optimal diet of fatty acids. Some researchers pre fer to use an omega-3 index, which is the sum of two omega-3 fatty acids: EPA and DHA. Evidence suggests that the omega-3 index is a helpful tool in predicting a person’s risk of coronary heart disease and sudden cardiac death (https://doi.org/10.1016/j.atherosclerosis.2017.05.007). Despite advances in understanding fatty acid metab olism and the role of dietary components in inflammation and disease, many aspects remain unknown. Future studies will continue to parse out the roles of individual fatty acids in the body and determine the optimal levels for health. The effects of ARA are complex. A systematic review in 2019, found that higher levels of ARA were not associ ated with better or worse health outcomes. People who consumed more than the typical amount of ARA (100-200 mg per day) up to between 1,000 and 1,500 mg per day did not experience adverse effects on their blood lipids, immune system function, or inflammation. Interestingly, a small study of elderly Japanese men indicated that ARA may counteract age-related cognitive decline (https://doi. org/10.1017/S0007114519000692). The complex effects of omega-6 fatty acids has led

cytokines, which circulate throughout the body, including the joints, and contribute to chronic conditions like OA over time. “It could take 20 years to develop osteoarthritis,” he said. Jeffries emphasized that both aging and obesity are gener ally associated with increased systemic inflammation. “As we age, our immune system tends to become more inflammatory all over the body, and obesity induces increased inflammation all over the body, and both of those things result in increased rates of OA.” Obesity and systemic inflammation play a role in the development of many diseases beyond OA. People who are obese have higher rates of hypertension, type 2 dia betes, heart disease, and some cancers (https://tinyurl. com/5085085). “It is hard to find a disease that is not impacted by metabolic function and obesity, and as we dig down further, dietary composition,” Guilak said. THE FUTURE OF FAT-1 GENE THERAPY Obesity remains a significant challenge in America. In 2023, more than 20 percent of adults in the US were obese, with the highest rates in the Midwest and South. In 23 states, more than one in three adults was obese (https://tinyurl. com/9154189). Available treatments for obesity include diet modifi cations, exercise, bariatric surgery, and GLP-1 agonists like Semaglutide. Each treatment option comes with challenges. Lifestyle modifications can be difficult to maintain over the long term, while medications can have side effects, and sur gery is invasive and costly. There may eventually be a gene therapy available to treat obesity. Researchers have only studied fat-1 gene therapy in mice and pigs, but Guilak sees a future where this type of gene ther apy may be available to treat people. Gene therapies come with risks and often significant monetary costs. “We would think about it only in really extreme cases where diet and exercise are not appropriate or would not work,” he said. An example population would include patients who are obese, immobile, and at extreme health risk. Guilak also sees poten tial use for fat-1 gene therapy in obese pets with obesity-re lated health challenges. Future studies will detemine how fat-1 gene therapy may translate from mouse models to humans. Guilak’s team hopes to uncover how to regulate fat-1 gene therapy bet ter and address potential safety concerns. Notably, the mice that received fat-1 gene therapy in Guilak’s studies showed no adverse side effects. “In everything we measured, we only saw beneficial effects,” he said. “We are a long way away from get ting into human studies.” Kelly Carroll is an assistant professor at Bellarmine University and freelance writer and editor. She can be contacted at kcarroll@bellarmine.edu.