How Exercise Fights the Effects of Aging
New research in healthy volunteers indicates that high-intensity interval training stimulates muscle cells to boost production of mitochondrial proteins and delay the aging process at the molecular level. The Cell Metabolism findings are encouraging because with age, the energy-generating capacity of cells’ mitochondria slowly decreases.
To examine the molecular players involved in the benefits of exercise, investigators from the Mayo Clinic randomly assigned 36 men and 36 women from 2 age groups (18–30 years old and 65–80 years old) into 3 different exercise programs: high-intensity interval biking, strength training with weights, and a combination of strength training and interval training. By performing thigh muscle biopsies and various laboratory tests, the team found that all programs enhanced insulin sensitivity and lean mass, but only high-intensity interval training and combined training improved aerobic capacity and skeletal muscle mitochondrial respiration.
The younger and older volunteers in the interval training group experienced a 49% and 69% increase in mitochondrial respiration, respectively. The interval training was less effective at improving muscle strength, however.
By comparing proteomic and RNA-sequencing data from people on different exercise programs, the researchers found evidence that exercise encourages cells to make more RNA copies of genes coding for mitochondrial proteins and proteins responsible for muscle growth. High-intensity training revealed a more robust increase in gene transcripts than other exercise modalities, and it also reversed many age-related differences in protein production and increased mitochondrial protein synthesis.
Increases in certain mitochondrial and ribosomal proteins were greater relative to changes in RNA content, indicating an increase in the synthesis rate of proteins. This suggests that exercise adaptations are regulated to a greater extent at the posttranscriptional level. The investigators also found a lowering of posttranslational protein damage following exercise training that may improve the functional quality of proteins.
Statins May Help Combat Cancer
In a screen of ≈9000 biologically active compounds, 3 different statins were the top candidates for promoting the depletion of mutant p53. Unlike normal p53, which has been dubbed the guardian of the genome and which suppresses tumors through DNA repair and other mechanisms, mutant p53 is a common driver of many types of cancer.
In a Nature Cell Biology study, investigators at the University of Kansas Medicine Center found that statins exert their effects on mutant forms of p53 by preventing it from binding to DNAJA1. This heat shock protein protects misfolded p53 from an enzyme that flags damaged or misshapen proteins for destruction. By preventing mutant p53 from binding to DNAJA1, statins force the mutant proteins to remain unprotected. The mevalonate pathway, which helps statins reduce cholesterol, is also involved in preventing mutant p53 from binding to DNAJA1.
Importantly, statins had no effect on normal p53 protein stability; however, they worked only on structurally mutated (misfolded) p53 and not p53 mutated at the location where it binds to DNA. This may help explain why studies looking at statin use and cancer risk have been inconclusive.
Experiments in cell culture assays and in mice demonstrated that statins preferentially suppress mutant p53–expressing cancer cell growth, and their antitumor effects were synergistic with traditional chemotherapeutics. However, overexpression of DNAJA1 nullified statins’ effects on mutant p53.
The findings suggest that targeting DNAJA1 directly or using statins in conjunction with chemotherapy may help fight certain cancers.
Blood Cell Mutations May Play a Role in Atherosclerosis
By generating a mouse model of atherosclerosis, investigators have gained new insights into how one of the genes commonly mutated in blood cells as humans age affects plaque development. The gene, called TET2 (ten-eleven translocation 2), codes for an epigenetic regulatory enzyme that modulates hematopoietic stem and progenitor cell self-renewal, but its role in cardiovascular disease remains largely unexplored.
In a recent Science study, plaque formation accelerated in mice transplanted with bone marrow cells lacking the mouse counterpart of the gene (Tet2), likely through increasing macrophage-driven inflammation in the artery wall.
A team led by researchers at the Boston University School of Medicine found that in atherosclerosis-prone, low-density lipoprotein receptor–deficient mice, partial bone marrow reconstitution with Tet2-deficient cells led to a marked increase in atherosclerotic plaque size. Also, Tet2-deficient macrophages secreted elevated levels of an inflammatory cytokine called NLRP3 inflammasome–mediated interleukin-1β.
An inhibitor of the NLRP3 inflammasome protected against atherosclerosis to a greater extent in mice reconstituted with Tet2-deficient cells than in other mice.
The findings suggest that TET2 mutations might be targeted to help prevent or treat atherosclerosis. Blocking interleukin-1β or the NLRP3 inflammasome may be other effective strategies in individuals carrying TET2 mutations. Importantly, neutralizing anti-interleukin-1β antibodies are currently being evaluated in cardiovascular clinical trials.
The new results also indicate that genetic analyses of blood samples could add to the predictive value of traditional cardiovascular risk factors, such as high cholesterol, hypertension, diabetes mellitus, and smoking.
Circulation is available at http://circ.ahajournals.org.
- © 2017 American Heart Association, Inc.