Mitochondrial energy metabolism and ageing

Abstract

Ageing can be defined as "a progressive, generalized impairment of function, resulting in an increased vulnerability to environmental challenge and a growing risk of disease and death". Ageing is likely a multifactorial process caused by accumulated damage to a variety of cellular components. During the last 20 years, gerontological studies have revealed different molecular pathways involved in the ageing process and pointed out mitochondria as one of the key regulators of longevity. Increasing age in mammals correlates with increased levels of mitochondrial DNA (mtDNA) mutations and a deteriorating respiratory chain function. Experimental evidence in the mouse has linked increased levels of somatic mtDNA mutations to a variety of ageing phenotypes, such as osteoporosis, hair loss, graying of the hair, weight reduction and decreased fertility. A mosaic respiratory chain deficiency in a subset of cells in various tissues, such as heart, skeletal muscle, colonic crypts and neurons, is typically found in aged humans. It has been known for a long time that respiratory chain-deficient cells are more prone to undergo apoptosis and an increased cell loss is therefore likely of importance in the age-associated mitochondrial dysfunction. In this review, we would like to point out the link between the mitochondrial energy balance and ageing, as well as a possible connection between the mitochondrial metabolism and molecular pathways important for the lifespan extension.

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

“…The salutary healthful aging properties of the RGS14 KO are mediated by BAT, involving a SIRT3 mechanism and its ability to improve metabolism and mitochondrial function, also known to mediate healthful aging (Bratic & Trifunovic, 2010; Brewer, Gibbs & Smith, 2016; Herranz et al., 2010). The latter point was confirmed by experiments with BAT transplants, which reversed the phenotypes of the RGS14 KO and WT, such that the WT with the BAT transplant did not exhibit the adverse phenotype of aging and demonstrated improved cold exposure tolerance and oxygen consumption, whereas the RGS14 KO donors no longer possessed these features of healthful aging.…”

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

“…Furthermore, some, but not all, studies have indicated a role for IRS2 gene variants in the pathogenesis of obesity and obesity-associated insulin resistance (Sesti et al 2001;Stefan et al 2003). Indeed, we have recently found that subjects with one or two IRS2 Asp alleles displayed a greater chance of living between 96 and 104 years of age (Barbieri et al 2010) Recent experimental evidences suggest that the effect of the insulin IGF1 signaling pathway on life span may be partially mediated by regulating the expression of uncoupling protein 2 (UCP2) (Bratic and Trifunovic 2010;Andrews et al 2005) In flies, over-expressing human UCP2 (hUCP2) to adult neurons resulted in decreased oxidative damage and extended life span without compromising fertility or physical activity (Fridell et al 2005). Furthermore, a very recent study has demonstrated that the absence of UCP2 shortens life span in wild-type mice, and the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals (Andrews and Horvath 2009).…”

AMPK agonist AICAR improves cognition and motor coordination in young and aged mice

“…In muscle, a notable effect was on mitochondrial gene expression. Mitochondria are key regulators of longevity (Bratic and Trifunovic 2010) and become less numerous with age, and membrane potential decreases. Mice with higher proton conductance across skeletal muscle inner mitochondrial membrane live longer (Bratic and Trifunovic 2010).…”

“…Mitochondria are key regulators of longevity (Bratic and Trifunovic 2010) and become less numerous with age, and membrane potential decreases. Mice with higher proton conductance across skeletal muscle inner mitochondrial membrane live longer (Bratic and Trifunovic 2010). In muscles, the increase in energy metabolism is evidenced by the up-regulation of genes directly involved in mitochondrial electron transport chain: complex I (NDUFA5, NDUFB9, NDUFB4) and complex IV, and also an up-regulation of complex II (SDHD); moreover, also Krebs Cycle is enhanced, both by complex II itself and by the AcCoA indirectly produced by the overexpression of DLD (Harris et al 1997).…”