Abstract
Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched wild-type controls. Mtbp haploinsufficiency significantly increased longevity and maximal survival in mice. Reduced levels of Mtbp did not alter locomotor activity, litter size, or body size, but Mtbp heterozygous mice did exhibit elevated markers of metabolism, particularly in the liver. Mtbp+/− mice also had a significant delay in spontaneous cancer development, which was most prominent in the hematopoietic system, and an altered tumor spectrum compared to Mtbp+/+ mice. Therefore, the data suggest Mtbp is a regulator of longevity in mice that mimics some, but not all, of the properties of Myc in aging.
Highlights
Aging is a complex biological process controlled by both environmental and genetic factors [1]; twin studies suggest 20-30% of lifespan variation is genetic [2, 3]
Since Myc+/- mice have increased longevity [8] and we have shown that Mtbp is a positive regulator of Myc [22, 23], we investigated the contribution of Mtbp to longevity using a cohort of littermate-matched Mtbp+/+ and Mtbp+/- mice
Mtbp heterozygous mice had increased longevity compared to wild-type controls, exhibiting a median survival of 785 days compared to 654 days (p=0.0013; Figure 1A, Supplemental Figure S1), a 20% increase
Summary
Aging is a complex biological process controlled by both environmental and genetic factors [1]; twin studies suggest 20-30% of lifespan variation is genetic [2, 3]. While Myc has been implicated in processes such as stem cell maintenance, differentiation, and apoptosis, Myc transcriptional activity is closely linked to cell-cycle progression and the vast metabolic machinery required for cellular proliferation [6, 7, 11]. Myc regulates mitochondrial biogenesis through expression of genes such as Pgc1α and Pgc1β (peroxisome proliferation activated receptor gamma coactivator 1-alpa and beta), providing sufficient mitochondria to maintain increased cellular metabolism [12]. Myc increases overall cellular energy flux by upregulating glycolysis and glutaminolysis through transcriptional activations of target genes like hexokinase 2 (Hk2) and glutaminase (Gls; [13,14,15,16]). Myc increases overall protein synthesis [19], a known modulator of longevity [20], through regulation of genes like nucleolin (Ncl) that control ribosomal assembly [21]
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