The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor.

The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hypoglycemia remain unclear and the subject of much debate. In this review, the molecular basis of the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular lesions and injury are discussed. Further, we review the potential role of the serum response factor (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins.

Does p49/STRAP, a SRF-binding protein (SRFBP1), modulate cardiac mitochondrial function in aging?

p49/STRAP (SRFBP1) is a transcriptional regulator that has been implicated in cardiac aging. p49/STRAP has a SRF binding domain and a BUD22 domain (which modulates cellular growth rate and cell size). We have observed that p49/STRAP alters the intracellular NAD/NADH ratio and induces protein deacetylation. Here we report that p49/STRAP overexpression caused the deacetylation of histone H4 on lysine 16 (H4K16) and suppressed the expression of PGC-1α as well as mitofusin-1 and mitofusin-2 at both the mRNA and protein levels. P49/STRAP also reduced mitochondrial size, mitochondrial membrane potential and the mitochondrial oxygen consumption rate. We noted that P49/STRAP expression was increased in the old versus young adult mouse hearts and also increased with advancing population doubling levels in cultured human umbilical vein endothelial cells (HUVECs). It is therefore very plausible that increased expression of p49/STRAP in late life may alter the status of histone acetylation and impact mitochondrial dynamics and thereby reduce mitochondrial function and cardiac performance during mammalian senescence.

Elevated oxygen consumption rate in response to acute low-glucose stress: Metformin restores rate to normal level.

Cardiovascular disease (CVD) continues to be the leading cause of mortality among all age demographics in the United States, with the highest occurrence in populations aged 65 and older. Glucose levels, particularly hyperglycemia, are associated with the premature onset of age-related diseases including CVD. A major challenge in the treatment of elderly patients with chronically elevated blood glucose is the frequency of hypoglycemic episodes. Molecular mechanisms of hypoglycemia remain unclear, but are associated with premature onset of age-related-diseases. Here we report a mitochondrial metabolic profile assessing short-term (up to six hours) and longer-term (12-24h) durations of low-glucose stress. We observed that the anti-diabetic biguanide and mitochondrial complex I inhibitor, metformin, can lower and restore the elevated oxygen consumption rate during shorter-term glucose stress to levels similar to that of cells cultured in normal glucose. This effect appears, in part, to involve activation of the 5' AMP-activated protein kinase (AMPK).

MicroRNA Clusters in the Adult Mouse Heart: Age-Associated Changes.

The microRNAs and microRNA clusters have been implicated in normal cardiac development and also disease, including cardiac hypertrophy, cardiomyopathy, heart failure, and arrhythmias. Since a microRNA cluster has from two to dozens of microRNAs, the expression of a microRNA cluster could have a substantial impact on its target genes. In the present study, the configuration and distribution of microRNA clusters in the mouse genome were examined at various inter-microRNA distances. Three important microRNA clusters that are significantly impacted during adult cardiac aging, the miR-17-92, miR-106a-363, and miR-106b-25, were also examined in terms of their genomic location, RNA transcript character, sequence homology, and their relationship with the corresponding microRNA families. Multiple microRNAs derived from the three clusters potentially target various protein components of the cdc42-SRF signaling pathway, which regulates cytoskeleton dynamics associated with cardiac structure and function. The data indicate that aging impacted the expression of both guide and passenger strands of the microRNA clusters; nutrient stress also affected the expression of the three microRNA clusters. The miR-17-92, miR-106a-363, and miR-106b-25 clusters are likely to impact the Cdc42-SRF signaling pathway and thereby affect cardiac morphology and function during pathological conditions and the aging process.