Fight Aging!

Here researchers look at some of the changes wrought in the metabolism of fat tissue, both over the course of aging, and under conditions of calorie restriction. Calorie restriction is the practice of eating fewer calories while still obtaining optimal levels of micronutrients. It has been shown to extend life in near all species and lineages tested to date. In the short term in humans it considerably improves measures of health, and over the long term is expected to greatly reduce incidence of age-related disease.

Understanding exactly how calorie restriction produces these benefits is a challenge, since it changes near every aspect of metabolism. Wading through the complexity of cellular biology in search of definitive proof and root causes has proven to be a sizable undertaking. Just look at the much-hyped investigation of sirtuins over the past decade or so, for example, and that is just one tiny slice of the molecular biochemistry relevant to calorie restriction. My prediction is that attempts to understand the calorie restriction response and other common altered states of metabolism in mammals will still be ongoing well into the era of widespread availability of rejuvenation therapies based on the SENS vision, as implementing treatments that repair known forms of cell and tissue damage is a much simpler undertaking than trying to recreate or improve upon the changes created by calorie restriction.

It has been long established that aging is the greatest risk factor for a range of diseases. Caloric restriction (CR) is a dietary intervention that delays aging and extends the period of health in diverse species. One of the hallmarks of caloric restriction is the marked reduction in adiposity, a consequence that may be important in the mechanisms of CR given the endocrine function of adipose tissue. Adipokines and lipokines secreted from white adipose tissue impact peripheral tissue fuel utilization and the balance of energy generation from lipid or carbohydrate sources. However, it is unclear what effect aging has on adipose tissue metabolic integrity and how that relates to secretion of systemic regulatory factors. Prior studies of gene expression in adipose tissues from old rats and adult mice show that CR induces expression of genes involved in multiple aspects of metabolism. A further difference includes the increased circulating levels of the adipose tissue-derived peptide hormone adiponectin with long-term stringent (40%) CR.

In order to understand whether age-related changes in adiposity are associated with a change in adipose tissue function, we undertook a cross-sectional mouse study focusing on adipose tissue metabolism and circulating levels of adipose tissue-derived signaling molecules. To capture the trajectory of aging, the study involved adult, late-middle-aged, and advanced-aged C3B6F1 hybrid mice. Parallel groups of mice on modest (16%) CR taken at each age served to uncover aspects of adipose tissue aging that were responsive to delayed aging. We investigated the relationship between adiposity, adipocyte size, and adiponectin levels at three age groups of mice on control or CR diets. We determined whether differences with age and diet were associated with changes in factors downstream of adiponectin and factors that connect with adiponectin signaling including NAD metabolism. To investigate differences in adipose tissue lipid metabolism, we profiled serum lipids including free fatty acids that are derived from adipose tissue. The goal of these studies was to determine how age and CR impacted adipose tissue function beyond simple differences in adiposity and whether relationships between adipocyte size and secretory profiles were sustained with age or altered with CR.

Adiposity and the relationship between adiposity and circulating levels of the adipose-derived peptide hormone adiponectin were age-sensitive. CR impacted adiposity but only levels of the high molecular weight isoform of adiponectin responded to CR. Activators of metabolism including PGC-1a, SIRT1, and NAMPT were differentially expressed with CR in adipose tissues. Although age had a significant impact on NAD metabolism, the impact of CR was subtle and related to differences in reliance on oxidative metabolism. The impact of age on circulating lipids was limited to composition of circulating phospholipids. In contrast, the impact of CR was detected in all lipid classes regardless of age, suggesting a profound difference in lipid metabolism. These data demonstrate that aspects of adipose tissue metabolism are life phase specific and that CR is associated with a distinct metabolic state, suggesting that adipose tissue signaling presents a suitable target for interventions to delay aging.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12575/full