In Nature Aging, researchers have discovered how growth differentiation factor 3 (GDF3), a cytokine that increases with aging, is related to more inflammatory macrophages in older animals.
Fat and inflammation
We have recently reported on a potential treatment for visceral fat, as this kind of fat is known to generate health problems, including an increase in inflammation [1]. Macrophages are the cause of some of this inflammation, which also makes fat loss more difficult; this effect has been linked to the GDF3 signaling axis [2].
GDF3 has been heavily studied in multiple contexts, including aging. Unsurprisingly, other research has linked it to fat gain [3], but it has also been found to be effective against blood sepsis [4] and even encourages muscle regeneration in older organisms [5]. As a member of the TGF-β superfamily, it acts on SMAD, a group of molecules that modify gene expression and help to manage chromatin [6], which governs the availability of DNA.
GDF3 changes toxic shock response
In their first experiment, the researchers challenged young and old mice with lipopolysaccharide (LPS), a toxic compound that encourages inflammation. Unsurprisingly, the old mice reacted more strongly than the younger mice, reducing their body temperatures and increasing their numbers of inflammatory macrophages compared to other macrophage types. Gdf3, correspondingly, also substantially increased in the older mice.
The researchers then created a breed of mice that don’t express Gdf3. These mice had few differences from their unmodified counterparts, including in adipocytes, and there were no changes in metabolism. However, among older animals, their numbers of inflammatory macrophages were significantly lower than those of wild-type mice, and they did not have the inflammatory phenotype that makes fat burning difficult. Old Gdf3-knockout mice also appeared to have healthier responses to LPS than old wild-type mice; younger mice saw no benefit.
Animals that had Gdf3 knocked out of only their bone marrow (myeloid) cells had significant reductions in multiple inflammatory factors, including IL-1b and IL-6. In old age, these animals also had significant improvements in glucose metabolism, a better ability to burn fat, and less strong reactions to LPS.
The researchers then attempted to treat GDF3 in older mice by using JQ1 to inhibit BDF4, which binds to GDF3. Older mice treated with JQ1 did not develop hypothermia upon LPS injection the way younger mice did, and they had fewer inflammatory macrophages. These results suggest that GDF3 is treatable.
Changing what genes are accessible
These results were found to be directly related to SMAD. Increasing GDF3 levels also increased the phosphorlyzation of SMAD2/3, which was found to lead to the increased inflammation in macrophages. The researchers confirmed this by directly suppressing SMAD3, which stopped the negative effects of GDF3 in the macrophages of old mice but did not affect younger mice. This suppression also inhibited other gene expressions in young mice, but those effects were not found in the older mice, leading the researchers to conclude that SMAD3, and GDF3, affect different pathways with aging.
Further work found that chromatin remodeling was a significant part of this change. Comparing old murine macrophages with and without Gdf3 revealed significant differences in these cells’ chromatin, which significantly altered which genes were accessible. Not only was there a significant decrease in chromatin-related inflammation in the Gdf3-knockout group, there was significant overlap between genetic pathways that were more accessible in the Gdf3-expressing macrophages and genetic pathways related to aging.
The researchers admit their study’s limitations, most notably that this research only involved mice and murine cells, with no human cells being used. Additionally, GDF3 serves vital biological functions, including in the immune system, and its effects on human beings may be different from those on lab mice kept in a controlled environment. Further work will determine if people have the same age-related changes in GDF3/SMAD function as mice do, along with whether or not this compound can be targeted to fight inflammaging and help people live longer.
Literature
[1] Carey, A., Nguyen, K., Kandikonda, P., Kruglov, V., Bradley, C., Dahlquist, K. J., … & Camell, C. D. (2024). Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis. Cell reports, 43(3).
[2] Camell, C. D., Sander, J., Spadaro, O., Lee, A., Nguyen, K. Y., Wing, A., … & Dixit, V. D. (2017). Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature, 550(7674), 119-123.
[3] Wang, W., Yang, Y., Meng, Y., & Shi, Y. (2004). GDF-3 is an adipogenic cytokine under high fat dietary condition. Biochemical and biophysical research communications, 321(4), 1024-1031.
[4] Wang, P., Mu, X., Zhao, H., Li, Y., Wang, L., Wolfe, V., … & Fan, G. C. (2021). Administration of GDF3 into septic mice improves survival via enhancing LXRα-mediated macrophage phagocytosis. Frontiers in immunology, 12, 647070.
[5] Patsalos, A., Simandi, Z., Hays, T. T., Peloquin, M., Hajian, M., Restrepo, I., … & Nagy, L. (2018). In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury. Aging cell, 17(5), e12815.
[6] Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., … & Vallier, L. (2018). The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency. Nature, 555(7695), 256-259.
View the article at lifespan.io
