Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Abstract

To provide a global analysis of gene expression in the aging heart, we monitored the expression of 9,977 genes simultaneously in 5-and 30-month-old male B6C3F1 mice by using high-density oligonucleotide microarrays and several statistical techniques. Aging was associated with transcriptional alterations consistent with a metabolic shift from fatty acid to carbohydrate metabolism, increased expression of extracellular matrix genes, and reduced protein synthesis. Caloric restriction (CR) started at 14 months of age resulted in a 19% global inhibition of age-related changes in gene expression. Interestingly, CR also resulted in alterations in gene expression consistent with preserved fatty acid metabolism, reduced endogenous DNA damage, decreased innate immune activity, apoptosis modulation, and a marked cytoskeletal reorganization. These observations provide evidence that aging of the heart is associated with specific transcriptional alterations, and that CR initiated in middle age may retard heart aging by inducing a profound transcriptional reprogramming.W hen started either early in life or at middle age, caloric restriction (CR) increases average and maximum lifespan, and reduces the incidence and delays the onset of spontaneous cancers and several other age-related diseases (1). Additionally, CR reduces the age-associated increase in reactive oxygen species (ROS)-induced molecular damage (2-5). Previously, we have used high-density oligonucleotide arrays to define aging and CR-related transcriptional alterations in mouse skeletal muscle (6) and brain (7). These reports provided evidence for an age-associated stress response characterized by the induction of heat-shock factors and other oxidative stress-induced transcripts. CR prevented these age-related alterations completely or partially. Both studies provided further support for the concept that oxidative stress may be an important, and perhaps underlying cause of the aging process of postmitotic tissues.The cardiac myocyte is the most energy demanding cell in the body, contracting constantly, 3 billion times or more in the average human lifespan (8), requiring large supplies of high-energy phosphates (9). Age-related changes in human and rodent hearts include a reduction in the number of myocytes (10, 11), myocyte hypertrophy (11, 12), cardiac fibrosis (13), lipofuscin pigment accumulation (14), a reduction in calcium transport across sarcoplasmic reticulum membrane (15), and alterations in the response to ␤-adrenergic stimulation (16). Collectively, these alterations likely contribute to age-related heart diseases being the leading cause of mortality in the U.S. (17). CR reduces the severity of spontaneous cardiomyopathy in male Sprague-Dawley rats (18) and prevents age-associated alterations in late diastolic function in B6D2F 1 mice (19). At the molecular level, CR reduces the concentration of both 8-hydroxydeoxyguanosine in DNA (20) and dityrosine cross-linking of proteins (21) in the heart of aging mice, and prevents somatic mitochondrial genomic rear...

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

“…In other organisms including mouse, the opposite correlation between fat storage and life span was also observed (44). The up-regulation of a TAG lipase and consequently down-regulation of TAG in ctbp-1(ok498) may reflect a possible change in energy utilization, which was implicated in caloric restriction animals and long-lived Snell dwarf mouse (45,46). Thus, the increased expression of LIPS-7 in the ctbp-1 mutant may contribute to life span extension by directly impacting energy metabolism and/or by changing lipid composition, membrane fluidity and signaling pathways.…”

Expression of the Pro-apoptotic Genegadd153/chop Is Elevated in Liver with Aging and Sensitizes Cells to Oxidant Injury

“…In that study, CR did not alter the effect of aging on gadd153 expression. By using a similar approach to examine age-related changes in gene expression in mouse heart, it was recently reported that gadd153 expression is not affected by aging but is reduced Ͼ3-fold by CR (49). Such disparate findings point to important organ/cell type-specific differences in the aging process of mammals.…”

Uncoupling the relationship between fatty acids and longevity

“…The intracellular availability of fatty acids would be an important factor here. Indeed, several genes involved in fatty acid transport to the mitochondria are downregulated in aging (28). These novel findings signify that fatty acids may play an important regulatory role in reducing oxidative stress generation and, thus, the process of physiological aging.…”