Transcriptional response to aging and caloric restriction in heart and adipose tissue

Abstract

SummarySustained caloric restriction (CR) extends lifespan in animal models but the mechanism and primary tissue target(s) have not been identified. Gene expression changes with aging and CR were examined in both heart and white adipose tissue (WAT) of Fischer 344 (F344) male rats using Affymetrix® RAE 230 arrays and validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on 18 genes. As expected, age had a substantial effect on transcription on both tissues, although only 21% of cardiac age-associated genes were also altered in WAT. Gene set enrichment analysis revealed coordinated small magnitude changes in ribosomal, proteasomal, and mitochondrial genes with similarities in aging between heart and WAT. CR had very different effects on these two tissues at the transcriptional level. In heart, very few age-associated expression changes were affected by CR, while in WAT, CR suppressed a substantial subset of the age-associated changes. Genes unaltered by aging but altered by CR were identified in WAT but not heart. Most interestingly, we identified a gene expression signature associated with mammalian target of rapamycin (mTOR) activity that was down-regulated with age but preserved by CR in both WAT and heart. In addition, lipid metabolism genes, particularly those associated with peroxisome proliferator-activated receptor γ γ γ γ (PPARγ γ γ γ )-mediated adipogenesis were reduced with age but preserved with CR in WAT. These results highlight tissue-specific differences in the gene expression response to CR and support a role for CR-mediated preservation of mTOR activity and adipogenesis in aging WAT.

Biological aging alters circadian mechanisms in murine adipose tissue depots

“…While the majority of genes were induced 2-fold in young vs. older cardiac tissue (82%), only a minority of genes displayed this pattern in adipose tissue (47%) (Linford et al 2007). Of these expressed transcripts, only 10% (WAT) or 21% (cardiac) of the total were common to both tissues (Linford et al 2007). Using a similar analytical method, the relative expression was compared between microarrays collected at multiple time points from BAT, iWAT, and liver of younger and older mice.…”

“…p values were determined by two-tailed Student's t test Biological aging differentially modulates a subset of expressed genes in BAT, iWAT, and liver Biological aging has been reported to modulate adipose and cardiac gene expression between young and old rats fed ad libitum (Linford et al 2007). While the majority of genes were induced 2-fold in young vs. older cardiac tissue (82%), only a minority of genes displayed this pattern in adipose tissue (47%) (Linford et al 2007). Of these expressed transcripts, only 10% (WAT) or 21% (cardiac) of the total were common to both tissues (Linford et al 2007).…”

“…Similar studies have evaluated the transcriptome in adipose tissue as a function of aging and/or caloric restriction in rodent models (Higami et al 2004;Fu et al 2006;Linford et al 2007;Swindell 2008). Studies have examined 10-11-month-old male C57BL/6 mice maintained under control or long-term (9-month) caloric restriction (Higami et al 2004).…”

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…We proceeded to also analyze mTORC1 signaling in white adipose tissue and heart, tissues in which mTOR signaling has been predicted to decrease with age based on transcriptional profiling (Linford et al ., 2007). Surprisingly, we observed a massive increase in S6 phosphorylation in adipose tissue, with phosphorylation of S6 increasing three‐fold in Middle‐aged and Old males and approximately six‐fold in Middle‐aged and Old females (Fig.…”

“…(2011) determined that mTORC1 signaling in liver and skeletal muscle decreases during aging. While this study stands alone in reporting a decrease in mTORC1 substrate phosphorylation during aging, it is supported by microarray data from rats which identified a transcriptional downregulation of mTOR signaling with aging in the heart and adipose tissue of F344 (Fischer 344) rats (Linford et al ., 2007). Transcriptional profiling of human blood likewise identified an age‐associated decrease in mTOR signaling (Harries et al ., 2012).…”