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Overall, carbohydrates showed negative associations across life-extending treatments in plasma and liver (Figure 5). This finding is consistent with other studies, which have shown that caloric restriction causes liver glucose levels to drop (Kirk et al. 2009), while the liver prevents blood sugar levels from dropping too steeply through gluconeogenesis. Other carbohydrates also showed declines proportional to extended lifespan in male liver, including as maltose, sorbitol, dexoypentitol, lactose, sophorose, and fructose. In contrast, fructose-6-phosphate, fructose-1-phosphate, galactonic acid, phosphogluconic acid, myo-inositol, trehalose, ribitol, galacto-N-biose, threonic acid, and glycerol-N-acetyl glucose were positively associated with increased lifespan in mice (Appendix S2). Hence, rather than responding as a class of compounds, these sugars responded in pathway-specific manner to lifespan-extending treatments. For example, the positive association of sugar phosphates indicated activation of glycolysis and pentose-phosphate pathways, whereas negatively associated sugars comprised degradation products of foods, glycans and starch in addition to sugar alcohols that have been associated with cancers of the liver, kidney, and brain (Ismail et al. 2020). Hence, both trends may be interpreted as better use of food-derived sugars, with less production of potentially harmful reduction products of sugar alcohols.
Phospholipids showed positive associations between metabolite levels and longevity increases across all tissues except plasma (Figure 5). This trend was particularly pronounced in male mice. Lysophosphatidylcholines diminished with higher lifespan effects in all organs except the adipose depots and male liver tissues, and female gonadal fat. Ether-based phospholipids showed a pattern similar to other phospholipid classes, making it unlikely that peroxisomes (the organelle in which ether-bonds are synthesized) play a specific role in these lifespan-extending treatments. Phospholipids are also under constant regulation and exert specific functions in different organs. We found negative associations of phosphatidylcholines (PC), the largest class of phospholipids, with extent of lifespan extension in both sexes in plasma (Figure 6C). Here, we saw decreases for both saturated and polyunsaturated fatty acyls groups, mostly with classic long-chain carbon lengths. These findings are consistent with observations of decreased levels of plasma lipoproteins and may help to explain the decreased levels of fat transport (albeit, specifically for long-chain- and very-long-chain PUFA-containing fats, see above). Other organs showed more complex regulation of PC lipid modulation under lifespan-extending interventions
Correspondingly, we found positive associations of free fatty acid levels with percent median lifespan extension in males across all organs (Figure 5), and in inguinal fat and kidney in female mice. The remaining diacylglycerides or lysophospholipids have been ascribed a range of physiological functions (Tan et al. 2020; Eichmann and Lass 2015). We found many PUFA-containing diacylglycerides to be specifically upregulated in inguinal fat tissues for both male and female mice in proportion to degree of lifespan increase (Figure 6B). Conversely, mostly saturated and mono-unsaturated diacylglycerides were negatively associated with lifespan extension in both plasma and liver for both sexes
These observations support the notion that lower levels of circulating glycerolipids are indicative of better health, including lower fatty liver levels, with a better accumulation of storage lipids in adipose tissues
3.3 Neutral Lipids Are Most Strongly Associated With Lifespan-Extensions in Mice
