Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis

Abstract

SummaryRecent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-α2 activity by 5′-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with β-guanidinopropionic acid (β-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging.

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats

“…It acts as a cancer chemoprevention agent [16], a powerful anti-inflammatory factor and an antioxidant agent [17,18]. Its cardiovascular properties, including inhibition of platelet aggregation and promotion of vasodilation by enhancing the production of NO [19] have also been described [15,20] and recent studies have reported its beneficial effects against ageing and metabolic diseases [21][22][23][24]. Resveratrol has been described as a potent activator of AMPK in several tissues and cell lines, i.e, HepG2 [24], C2C12 myotubes [25] neuronal cell lines and neurons [26].…”

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…In certain circumstances, such as aging, the mechanisms for why or how mitochondrial function and dynamics become abnormal are unknown (Petersen et al 2003;Reznick et al 2007). Regardless of the mechanism, however, data gleaned from signaling studies suggest that certain elements of these pathways can be leveraged to either prevent or attenuate a wide array of mitochondrial dysfunctions.…”

β‐Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP‐activated protein kinase‐dependent increase in autophagy

“…Guanidinopropionic acid feeding has been shown to increase mitochondrial biogenesis by elevated levels of PGC‐1α mRNA expression, mitochondrial density, δ‐ALAS mRNA expression, and cytochrome c protein expression (Reznick et al ., 2007). Our results demonstrate that β‐GPA decreases the level of LD and LDH, indicating the decreased glycolysis.…”

“…The finding that β‐GPA can activate AMPK in the brain is consistent with previous reports showing that β‐GPA increases the AMPK activity in peripheral tissues, such as skeletal muscle (Reznick et al ., 2007). We found that β‐GPA upregulated the AMPK activity in Drosophila , and this upregulation was ubiquitous, as the levels of phosphorylated AMPK were similarly upregulated in all main segments of Drosophila , such as heads, thoraces, and abdomens.…”

“…β‐Guanidinopropionic acid (β‐GPA) is a creatine analog. A wide range of pharmacological effects of β‐GPA have been reported, including increase in mitochondrial enzyme activities and biogenesis in muscle (Reznick & Shulman, 2006; Reznick et al ., 2007), and decrease in plasma glucose concentration and antihyperglycemic effect (Mukhina et al ., 2008). Rush et al .…”