In Aging Cell, researchers have described the chemical ways in which excessive visceral fat causes oxidative stress and cellular senescence.
Visceral fat is metabolically active
Metabolic syndrome, a host of intertwined disorders that include obesity and cholesterol imbalance, is known to have multiple harmful effects that lead to decreased lifespan. These include a propensity towards Type 2 diabetes along with the accumulation of fat around the organs (visceral fat), which is distinct from the fat under the skin (subcetaneous fat).
Visceral fat cells becoming senescent is a driver of metabolic syndrome, and removing those cells was found to alleviate some of the associated problems in a murine model [1]. Further work has found that these senescent fat cells lead to an increase in insulin resistance [2], the core driver of type 2 diabetes. Targeting these cells was found to alleviate insulin resistance in mice as well [3].
However, this paper notes that little research has endeavored to find what, precisely, is driving these fat cells to become senescent to begin with. Cells can be driven senescent through a large number of very well-explored factors, including toxins, radiation, the activation of cancer-related genes, telomere attrition, and oxidative stress. Oxidation, particularly of lipids (fats), is this paper’s focus.
Oxidating the membrane lipids of cells creates a class of compounds known as enals [4]. In a murine model of obesity, prior work found that these enals accumulate to surprisingly high levels in visceral fat [5]. This pro-senescent environment is accompanied by the downregulation of the enzymes that would normally impede this accumulation [6].
Enals, which last longer than reactive oxygen species in the body [7], easily pass through cellular membranes and readily react with proteins, including the nucleic acids of DNA. This causes carbonyl stress, which can damage DNA and protein function [8]. While the Campisi lab had investigated enals in senescence [9], these researchers sought a more focused and detailed investigation.
Harmful on many levels
In one of the first experiments, IMR90 cells, a commonly used line of lung fibroblasts, were exposed to one of three common enals over a week. Unsurprisingly, this quickly drove many of these cells senescent according to multiple biomarkers: SA-β-gal and p21 were both significantly upregulated, and one of the enals, 4-ONE, caused an increase in p16. This increase in senescence wasn’t accompanied by an increase in cellular death by apoptosis. The effects were similar on murine stem cells.
This research also confimed that 4-HNE, another of the most common enals, modifies proteins. Most of the altered proteins were from the mitochondria. Interestingly, cells seemed to be somewhat resistant to 4-HNE after the first exposure: 4 to 8 hours after this initial exposure, the number of these proteins spiked considerably, but administering it again on subsequent days di not lead to such an increase. However, they still suffered from mitochondrial dysfunction, being less able to produce ATP and properly use oxygen.
4-HNE is also toxic to the genome. γH2AX, a marker of DNA breakage, was increased four hours after exposure, and this drove the p53 and p21 pathways. This was attributed to the creation of a known mutagen [10].
As expected, exposure to enals also drove the formation of multiple SASP components. Unexpectedly, though, these were not driven by NF-κB signaling; in fact, the inflammatory cytokines that come from NF-κB, including IL-6 and IL-8, were downregulated instead. Not all of these SASP components were affected at the same time or the same rate.
These findings suggest that a disruption in normal protein folding and homeostasis, mitochondrial and metabolic stress, and phospholipid remodeling are features of cellular senescence that occur irrespective of what initiates the senescence.
Looking for a treatment
These researchers quickly discovered that in white fat tissue, older (24-26 months) mice have twice the amount of 4-HNE as younger (4-6 months) mice do. Mice fed a high-fat diet also have elevated amounts of enals, and treating these mice with L-carnosine, a compound that binds with enals, was able to alleviate some of their effects: this compound reduced some key biomarkers of metabolic syndrome, such as glucose tolerance and insulin resistance. However, its effects did not restore these obese mice close to a control group fed a healthy diet.
This research makes it clear that visceral fat is extremely dangerous over the long term, as it is a driver of multiple hallmarks of aging: genomic instability, mitochondrial dysfunction, and cellular senescence. While therapies might be developed to blunt its effects, it is clearly best never to accumulate it.
Literature
[1] Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., … & Kirkland, J. L. (2015). Targeting senescent cells enhances adipogenesis and metabolic function in old age. elife, 4, e12997.
[2] Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., … & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126.
[3] Wang, L., Wang, B., Gasek, N. S., Zhou, Y., Cohn, R. L., Martin, D. E., … & Xu, M. (2022). Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell metabolism, 34(1), 75-89.
[4] Catalá, A. (2009). Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chemistry and physics of lipids, 157(1), 1-11.
[5] Long, E. K., Olson, D. M., & Bernlohr, D. A. (2013). High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4-hydroxy-2-nonenal levels in a depot-specific manner. Free Radical Biology and Medicine, 63, 390-398.
[6] Curtis, J. M., Grimsrud, P. A., Wright, W. S., Xu, X., Foncea, R. E., Graham, D. W., … & Bernlohr, D. A. (2010). Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction. diabetes, 59(5), 1132-1142.
[7] Siems, W., & Grune, T. (2003). Intracellular metabolism of 4-hydroxynonenal. Molecular aspects of medicine, 24(4-5), 167-175.
[8] Yoval-Sánchez, B., & Rodríguez-Zavala, J. S. (2012). Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts. Chemical research in toxicology, 25(3), 722-729.
[9] Wiley, C. D., Sharma, R., Davis, S. S., Lopez-Dominguez, J. A., Mitchell, K. P., Wiley, S., … & Campisi, J. (2021). Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell metabolism, 33(6), 1124-1136.
[10] Minko, I. G., Kozekov, I. D., Harris, T. M., Rizzo, C. J., Lloyd, R. S., & Stone, M. P. (2009). Chemistry and biology of DNA containing 1, N 2-deoxyguanosine adducts of the α, β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chemical research in toxicology, 22(5), 759-778.
