Current nutritional and pharmacological anti-aging interventions.

Aging is the main risk factor for chronic diseases and disablement in human societies with a great impact in social and health care expenditures. So far, aging and, eventually, death are unavoidable. Nevertheless, research efforts on aging-associated diseases with the aim not only to extend life span but also to increment health span in an attempt to delay, stop and even reverse the aging process have not stopped growing. Caloric restriction extends both health and life span in several short-lived experimental models and has brought to light the role of different molecular effectors involved in nutrient sensing pathways and longevity. This opens the possibility of modulating these molecular effectors also in humans to increase longevity and health span. The difficulty to implement caloric restricted diets in humans has led to the development of new bearable diets such as time-restricted feeding, intermittent fasting or diets with limited amounts of some nutrients and to the search of pharmacological agents, targeted to the effectors that mediate the extension of life and health span in response to these anti-aging diets. Pharmacological approaches that eliminate senescent cells or prevent primary causes of aging such as telomere attrition also emerge as potential anti-aging strategies. In the present article, we review these possible nutritional and pharmacological interventions designed to mitigate and/or delay the aging process and to increase health and life span.

Differential Development of Inflammation and Insulin Resistance in Different Adipose Tissue Depots Along Aging in Wistar Rats: Effects of Caloric Restriction.

The prevalence of insulin resistance and type 2 diabetes increases with aging and these disorders are associated with inflammation. Insulin resistance and inflammation do not develop at the same time in all tissues. Adipose tissue is one of the tissues where inflammation and insulin resistance are established earlier during aging. Nevertheless, the existence of different fat depots states the possibility of differential roles for these depots in the development of age-associated inflammation and insulin resistance. To explore this, we analyzed insulin signaling and inflammation in epididymal, perirenal, subcutaneous, and brown adipose tissues during aging in Wistar rats. Although all tissues showed signs of inflammation and insulin resistance with aging, epididymal fat was the first to develop signs of inflammation and insulin resistance along aging among white fat tissues. Subcutaneous adipose tissue presented the lowest degree of inflammation and insulin resistance that developed latter with age. Brown adipose tissue also presented latter insulin resistance and inflammation but with lower signs of macrophage infiltration. Caloric restriction ameliorated insulin resistance and inflammation in all tissues, being more effective in subcutaneous and brown adipose tissues. These data demonstrate differential susceptibility of the different adipose depots to the development of age-associated insulin resistance and inflammation.

Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: effect of caloric restriction.

Aged Wistar rats present central insulin resistance associated with ageing. Several steps of the insulin signaling pathway have been described to be impaired in aged rats at hypothalamic level. In the present article we have explored possible alterations in protein tyrosine phosphatases (PTPs) involved in insulin receptor dephosphorylation, as well as pro-inflammatory pathways and serine kinases such as inhibitory kappa ß kinase-nuclear factor kappa-B (IKKß-NFκB), p38 mitogen-activated protein kinase (p38) and protein kinase C θ (PKCθ) that may also be involved in the decreased insulin signaling during ageing. We detected that ageing brings about a specific increase in insulin receptor tyrosine phosphatase activity and PTP1B serine phosphorylation. Increased association of PTP1B and leukocyte common antigen-related tyrosine protein phosphatase (LAR) with insulin receptor was also observed in hypothalamus from aged rats. Besides these mechanisms, increased activation of the IKKß-NFκB pathway, p38 and PKCθ serine/threonine kinases were also detected. These data contribute to explain the hypothalamic insulin resistance associated with ageing. Caloric restriction ameliorates most of the effects of ageing on the above mentioned increases in PTPs and serine/threonine kinases activities and points to age-associated adiposity and inflammation as key factors in the development of age-associated insulin resistance.

Leptin accumulation in hypothalamic and dorsal raphe neurons is inversely correlated with brain serotonin content.

Food intake and energy balance are among the functions regulated by serotonin in the brain. Recent studies have shown an interaction of serotonergic system with leptin, a protein released from adipose tissue that inhibits feeding behavior and increases fuel expenditure. In this study, leptin labeled with digoxigenin was injected in the lateral cerebral ventricle of 5 young adult rats (4months old) and 5 aged rats (24months old) to assess the effect of aging on the accumulation of exogenous leptin by raphe and hypothalamic neurons. Four aged rats showed an intense leptin accumulation in neuronal cell bodies, mainly at the level of the dorsal raphe nucleus. In contrast, only one young rat showed neuronal accumulation of leptin in dorsal raphe and hypothalamus. Low brain serotonin immunoreactivity was found in all animals with high neuronal leptin accumulation at the raphe nucleus, independently of their age. In contrast, high brain serotonin immunoreactivity was accompanied by a low neuronal accumulation of leptin. To determine whether differences in serotonin content were the cause of the differences in leptin accumulation an inhibitor of serotonin synthesis, p-chlorophenylalanine, was administered to young rats. Serotonin depletion resulted in an enhanced accumulation of leptin in raphe as well as in hypothalamic neurons. These findings indicate that serotonin regulates leptin uptake by neuronal cell bodies of the dorsal raphe and hypothalamus, this suggests that at least part of the effects of serotonin may be mediated by the regulation of neuronal trafficking in the brain.

Tissue-specific effects of central leptin on the expression of genes involved in lipid metabolism in liver and white adipose tissue.

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor alpha in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.