Fight Aging!

Calorie restriction extends healthy life in mice, and so does removing or blocking the activity of growth hormone through genetic engineering. The reasons for enhanced longevity in both of these cases are well studied but still far from fully understood, as both produce very broad alterations in the enormously complex processes of cellular metabolism. Trying both methods together is a way to perhaps shed some light on the more important mechanisms involved, however.

Ames dwarf (df/df) mice are homozygous for a spontaneous recessive mutation of the prophet of pituitary factor-1 (Prop1) gene, which inhibits development of three specific anterior pituitary cell types - somatotrophs, lactotrophs and thyrothrophs. The absence of these cell types in the df/df mice leads to deficiency of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH). Interestingly, however, these mutants live significantly longer (40-60%) and healthier lives compared to their normal siblings. Ames dwarf mice phenotypically appear normal at birth but they grow at a slower rate and reach only half of the normal adult body weight, compared to their normal littermates. These mutant mice also exhibit very low levels of insulin-like growth factor-1 (IGF-1) and thyroid hormones. Furthermore, they have a reduced body temperature, but their food and oxygen consumption per gram of body weight are increased. Ames dwarf mice are less prone to cancer. These mutants show increased insulin sensitivity and glucose tolerance, thus displaying no diabetic phenotype. Furthermore, Ames dwarf mutants have reduced response of skeletal muscle to high levels of insulin, which might be important for their control of glucose homeostasis and as well their positive effects in extended longevity

Calorie restriction (CR), is the only efficient intervention which delays aging and extends lifespan. Laboratory animals subjected to reduced caloric intake, exhibit a number of beneficial effects including extension of lifespan, reduced body weight, plasma glucose and insulin levels; and improved insulin sensitivity and health span. Studies in various animal species revealed that CR delays aging, decreases cholesterol levels and blood pressure. Studies involving mice and rats support the concept that CR delays the aging process and reduces the incidence of several age-related diseases including type 2 diabetes and cancer. In addition, it has been shown that the prolongation of life can be greater than 40% in mice under CR regimen; with even greater extension of longevity in non-mammalian models.

Based on extensive studies of CR and Prop1 mutation on insulin signaling, metabolism and aging there is some evidence that indicates that Ames dwarfism and CR may act through similar mechanisms but they are certainly not identical. We studied the effects of calorie restriction (CR) on the expression of insulin signaling genes in skeletal muscle and adipose tissue of normal and df/df mice. The analysis of genes expression showed that CR differentially affects the insulin signaling pathway in these insulin target organs. Moreover, results obtained in both normal and Ames dwarf mice indicate more direct effects of CR on insulin signaling genes in adipose tissue than in skeletal muscle. Interestingly, CR reduced the protein levels of adiponectin in the epididymal adipose tissue of normal and Ames dwarf mice, while elevating adiponectin levels in skeletal muscle and plasma of normal mice only.

Link: http://www.impactaging.com/papers/v6/n10/full/100700.html