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. 2015 Jan 29;160(3):477-88.
doi: 10.1016/j.cell.2014.12.016. Epub 2015 Jan 22.

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

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Free PMC article

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

Jeffrey W Hofmann et al. Cell. .
Free PMC article

Abstract

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

Figures

Figure 1
Figure 1. MYC Expression, Longevity, Body Mass and Composition
(A) MYC mRNA and protein expression. mRNA was measured by qRT-PCR. Protein was measured by immunoblotting of tail fibroblasts or by IF of liver sections. Fibroblasts: N=3, 3 months, females. Liver: N=3–5, 5–9 months, both sexes. (B) Survival of Myc+/+ (blue) and Myc+/− (red) mice. Each data point shows one animal (N, number of animals in each cohort). (C) Lifelong trends of whole body weights. Median weights (3-week sliding window) of the aging cohorts in (B). Inset: weights at 500 days and relative weights of Myc+/− animals. (D) Relative adiposity. Animals were scanned by micro-CT imaging. Left: volume of all white fat as percent of total volume of the animal. Right: volume of visceral fat as percent of total fat. N=6, 5 months. See also Figure S1 and Tables S1 and S2.
Figure 2
Figure 2. Metabolic Hormones, Fecundity and Cancer Incidence
(A–C) Levels of adiponectin, leptin, and free IGF-1 in plasma. Blood samples were collected after overnight fasting. N=5–12, 5 and 22 months, females. (D) Lifetime reproductive output. Myc+/− and Myc+/+ females (N=5) were bred with Myc+/+ males (left), and Myc+/− and Myc+/+ males (N=7–9) were bred with Myc+/+ females (right). (E) Sexual maturation of females. N=12–19. (F) Left: Cause of death determined by a veterinary pathologist. N=19 Myc+/+, 38 Myc+/−, both sexes. Right: Incidence of macroscopic cancer noted at time of autopsy (Myc+/+, 73.4%; Myc+/−, 53.7%; p=0.03). N=64 Myc+/+, 67 Myc+/−, both sexes. (G) Histopathological analysis was used to determine the spread (left; number of affected tissues) and severity (right; maximum grade) of lymphoma. N=12 Myc+/+, 27 Myc+/−, both sexes. See also Figure S2 and Table S3.
Figure 3
Figure 3. Transcriptome Analysis
(A) Gene expression changes. Three parameters were compared: genotype (Myc+/+, Myc+/−), age (5, 24 months) and tissue (liver, muscle, adipose). Genotype, age, and tissue comparisons are connected with diagonal, vertical and horizontal lines, respectively. The number of genes changing expression is shown above and below each line. Red numbers: genes upregulated in Myc+/+ versus Myc+/− animals (MYC activated genes); blue numbers: genes upregulated in Myc+/− versus Myc+/+ animals (MYC repressed genes). A 1.5-fold cutoff and a FDR threshold of <5% were used. N=5–8 male animals. (B) Effect of age on the transcriptome. Left panel: number of genes whose expression changes with age by more than 50% in either direction; hatched area represents genes in common between the two genotypes. Right panel: the median change in expression with age (expressed as %) across all expressed genes. (C) Meta-analysis. Differentially expressed genes in Myc+/− versus Myc+/+ animals were compared with genes similarly recovered in studies of calorie restriction, metformin, or resveratrol treatment (Martin-Montalvo et al., 2013; Pearson et al., 2008). Upward arrows indicate genes upregulated in the long-lived condition (and conversely for downward arrows). Expression in liver of old male mice was compared. Skeletal muscle showed the same trends. See also Figure S3 and Tables S4, S5 and S6.
Figure 4
Figure 4. Amelioration of Age-Associated Phenotypes
(A) Cardiac fibrosis was scored in ventricular cross sections using Masson’s trichrome stain. N=11–14, 22–24 months, both sexes. (B) Osteoporosis in females was assessed using micro-CT analysis. N=3–7, 5 and 22 months. (C) Trabecular spacing and number were scored by micro-CT, as above. (D) Liver sections were stained with Oil Red O. N=6, 5 and 24 months, males. (E) Gene expression in liver was measured by qRT-PCR. Intermediates in the cholesterol biosynthetic pathways are shown on the left, and the corresponding genes on the right. Data are normalized to Myc+/+ for each comparison. N=4, 24 months, males. (F) Total and non-esterified cholesterol in liver extracts and serum. Normalized to Myc+/+. N=5–6, 24 months, males. (G) Animals of average weight were chosen for rotarod tests, and their performance was corrected for their weight. N=3–4, 24 months, males. See also Figure S4.
Figure 5
Figure 5. Immunosenescence, Stress Defenses and Metabolic Activity
(A) Total T cells (CD3+) were analyzed by flow cytometry as % of total peripheral lymphocytes. N=8–12, 5 and 24 months, males. (B) Ratio of naive to memory T cells (CD44/CD44+), and (C) ratio of helper to killer T cells (CD4+/CD8+) were measured in the same samples. (D) Proportions of common myeloid and lymphoid progenitors (CMP, CLP), and short-term and long-term hematopoietic stem cells (ST-HSC, LT-HSC) were scored as % of Lin cells in bone marrow (tibia and femur). N=6, 16 months, females. Normalized to Myc+/+ for each comparison. (E) Ratio of CLP to CMP, and (F) ratio of ST-HSC to LT-HSC in the same samples. (G) 53BP1-positive cells were visualized by IF in liver sections. N=5–6, 5 and 25 months, males. (H) Apoptotic cells in liver were identified by IF with an antibody to cleaved caspase-3. N=6–8, 5 and 22 months, females. (I) F2 isoprostane levels were measured in liver extracts using gas chromatography and mass spectrometry. N=4–7, 5 and 23–27 months, males. (J) O2 consumption by young animals over a 24 hour period. Statistical significance in was computed using two-way ANOVA (time, genotype). Genotype factor was significantly different; p<0.001. N=8, 5 months, both sexes. (K) O2 consumption by old animals. P(genotype) <0.001. N=7–8, 17–22 months, males. See also Figure S5.
Figure 6
Figure 6. Spontaneous Activity, Energy Metabolism and Signaling Pathways
(A) Spontaneous home cage activity. Of the 4 categories of behaviors (micromovements, sleeping, consumption, and active behaviors), micromovements and active behaviors were statistically different. N=6, 16–18 months, males. (B) AMP concentrations in extracts of muscle. N=5–7, 25–30 months, both sexes. (C) AMP to ATP ratio in the same samples (B). (D) The ratio of phosphorylated (Thr172) to total AMPKα in muscle was determined by immunoblotting. Data are normalized to Myc+/+ for each comparison. N=4, 9–11 months, females; N=3, 25–30 months, both sexes. (E) Ribosomal RNA content of liver. N=4, 23–25 months, female. (F) Translation rates in live animals (liver) were assessed using 3H-phenylalanine incorporation into total protein. Muscle showed the same trend. N=5, 5–7 months; males. (G) The ratio of phosphorylated (Ser473) to total AKT in liver and muscle. N=4, 9–11 months, female (same samples as in D). Normalized to Myc+/+. (H) The ratio of phosphorylated (Ser235/236) to total S6 ribosomal protein in liver and muscle (same samples as in G. Normalized to Myc+/+. See also Figure S6.
Figure 7
Figure 7. The Effects of Myc on Healthspan and Longevity
(A) Phenotypes of Myc+/− mice demonstrating their interconnectedness and impact on healthspan (they key under the drawing applies to this panel only). (B) Pathways affected by Myc hypomorphism and their relationship to increased longevity. The components investigated in this report are highlighted in red.

Comment in

  • Growing old with Myc.
    Carroll PA, Eisenman RN. Carroll PA, et al. Cell. 2015 Jan 29;160(3):365-6. doi: 10.1016/j.cell.2015.01.018. Cell. 2015. PMID: 25635453 Free PMC article.

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