By Dr. Francis Collins
The struggle to maintain a healthy weight is a lifelong challenge for many of us. In fact, the average American packs on an extra 30 pounds from early adulthood to age 50. What’s responsible for this tendency toward middle-age spread? For most of us, too many calories and too little exercise definitely play a role. But now comes word that another reason may lie in a strong—and previously unknown—biochemical mechanism related to the normal aging process.
An NIH-led team recently discovered that the normal process of aging causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies show it also slows down metabolism, making it more difficult to burn fat. To see if reducing DNA-PK levels might rev up the metabolism, the researchers turned to middle-aged mice. They found that a drug-like compound that blocked DNA-PK activity cut weight gain in the mice by a whopping 40 percent!
Jay H. Chung, an intramural researcher with NIH’s National Heart, Lung, and Blood Institute, had always wondered why many middle-aged people and animals gain weight even when they eat less. To explain this paradox, his team looked to biochemical changes in the skeletal muscles of middle-aged mice and rhesus macaques, whose stage in life would be roughly equivalent to a 45-year-old person.
Their studies, published recently in Cell Metabolism, uncovered evidence in both species that DNA-PK increases in skeletal muscle with age . The discovery proved intriguing because the enzyme’s role in aging was completely unknown. DNA-PK was actually pretty famous for a totally different role in DNA repair, specifically its promotion of splicing the DNA of developing white blood cells called lymphocytes. In fact, lymphocytes fail to mature in mice without a working copy of the enzyme, causing a devastating immune disorder known as severe combined immunodeficiency (SCID).
Further study by Chung’s team showed that DNA-PK in the muscle acted as a brake that gradually slows down metabolism. The researchers found in these muscle cells that DNA-PK decreases the capacity of the mitochondria, the powerhouses that burn fat for energy. The enzyme also causes a decline in the number of mitochondria in these cells.
The researchers suspected that an increase in DNA-PK in middle age might lead directly to weight gain. If correct, then blocking the enzyme should have the opposite effect and help stop these mice from piling on the pounds.
Indeed, it did. When the researchers treated obese mice with a drug called a DNA-PK inhibitor, they gained considerably less weight while fed a high-fat diet. The treatment also protected the animals from developing early signs of diabetes, which is associated with obesity. Fortunately, there was no sign of trouble in the immune systems of middle-aged mice treated with the DNA-PK inhibitor, presumably because those essential DNA splicing events in lymphocytes had already occurred. Neither was there a sign of serious side effects, such as cancer.
As people age and their weight increases, they also tend to become less physically fit. The new evidence implicates DNA-PK in that process, too. Obese and middle-aged mice treated with the DNA-PK inhibitor showed increased running endurance. With treatment, they ran about twice as long on a tiny mouse treadmill than they would normally.
While the findings are in mice, they suggest that an increase in DNA-PK could explain why it becomes so frustratingly difficult for many of us to stay lean and fit as we age.
It also paves the way for the development of a new kind of weight-loss medication designed to target this specific biochemical change that comes with middle age.
Chung says they are now looking for DNA-PK inhibitors that might work even better than the one in this study. But given the fact that DNA-PK has other roles, testing its safety and effectiveness will take time.
While we await the results, the best course to help fight that middle-age spread hasn’t changed. Eat right and follow an exercise plan that you know you can stick to—it will make you feel better. Take it from me, a guy who decided eight years ago that it was time to shape up, stopped eating honey buns, got into a regular exercise program with a trainer to keep me accountable, and lost those 30 pounds. You can do it, even without a DNA-PK inhibitor!
 DNA-PK promotes the mitochondrial, metabolic, and physical decline that occurs during aging. Park SJ, Gavrilova O, Brown AL, Soto JE, Bremner S, Kim J, Xu X, Yang S, Um JH, Koch LG, Britton SL, Lieber RL, Philp A, Baar K, Kohama SG, Abel ED, Kim MK, Chung JH. Cell Metab. 2017 May 2;25(5):1135-1146.
Overweight and Obesity (National Heart, Lung, and Blood Institute/NIH)
Health Tips for Older Adults (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Jay H. Chung (National Heart, Lung, and Blood Institute/NIH)
NIH Support: National Heart, Lung, and Blood Institute; Office of the Director
DNA damage appears to be the primary underlying cause of cancer, and deficiencies in DNA repair genes likely underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to cancer.
PRKDC (DNA-PKcs) mutations were found in 3 out of 10 of endometriosis-associated ovarian cancers, as well as in the field defects from which they arose. They were also found in 10% of breast and pancreatic cancers.
Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily even more frequent than mutational defects in DNA repair genes in cancers.
DNA-PKcs expression was reduced by 23% to 57% in six cancers as indicated in the table.
|Cancer||Frequency of reduction in cancer||Ref.|
|Epithelial ovarian cancer||29%|||
It is not clear what causes reduced expression of DNA-PKcs in cancers. MicroRNA-101 targets DNA-PKcs via binding to the 3′- UTR of DNA-PKcs mRNA and efficiently reduces protein levels of DNA-PKcs. But miR-101 is more often decreased in cancers, rather than increased.
HMGA2 protein could also have an effect on DNA-PKcs. HMGA2 delays the release of DNA-PKcs from sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing chromosomal aberrations. The let-7a microRNA normally represses the HMGA2 gene.
In normal adult tissues, almost no HMGA2 protein is present. In many cancers, let-7 microRNA is repressed.
As an example, in breast cancers the promoter region controlling let-7a-3/let-7b microRNA is frequently repressed by hypermethylation. Epigenetic reduction or absence of let-7a microRNA allows high expression of the HMGA2 protein and this would lead to defective expression of DNA-PKcs.
DNA-PKcs can be up-regulated by stressful conditions such as in Helicobacter pylori-associated gastritis. After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma tissues.
The ATM protein is important in homologous recombinational repair (HRR) of DNA double strand breaks. When cancer cells are deficient in ATM the cells are “addicted” to DNA-PKcs, important in the alternative DNA repair pathway for double-strand breaks, non-homologous end joining (NHEJ). That is, in ATM-mutant cells, an inhibitor of DNA-PKcs causes high levels of apoptotic cell death. In ATM mutant cells, additional loss of DNA-PKcs leaves the cells without either major pathway (HRR and NHEJ) for repair of DNA double-strand breaks.
Elevated DNA-PKcs expression is found in a large fraction (40% to 90%) of some cancers (the remaining fraction of cancers often has reduced or absent expression of DNA-PKcs). The elevation of DNA-PKcs is thought to reflect the induction of a compensatory DNA repair capability, due to the genome instability in these cancers.(As indicated in the article Genome instability, such genome instability may be due to deficiencies in other DNA repair genes present in the cancers.)
Elevated DNA-PKcs is thought to be “beneficial to the tumor cells”, though it would be at the expense of the patient.
As indicated in a table listing 12 types of cancer reported in 20 publications, the fraction of cancers with over-expression of DNA-PKcs is often associated with an advanced stage of the cancer and shorter survival time for the patient. However, the table also indicates that for some cancers, the fraction of cancers with reduced or absent DNA-PKcs is also associated with advanced stage and poor patient survival.
DNA-PKcs is one of the key components of the NHEJ machinery. DNA-PKcs deficient mice have a shorter lifespan and show an earlier onset of numerous aging related pathologies than corresponding wild-type littermates.
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
- Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4.
- Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex.
- Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1.
To maintain energy homeostasis, mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A.
- mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at ‘Ser-758’, disrupting the interaction with AMPK and preventing activation of ULK1.
- Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP.
- mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor.
- Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1.
- Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1.
- Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906).
- mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.8 Publications
GO – Molecular functioni
- ATP binding Source: UniProtKB-KW
- kinase activity Source: MGI
- phosphoprotein binding Source: UniProtKB
- protein domain specific binding Source: Ensembl
- protein kinase activity Source: WormBase
- protein kinase binding Source: Ensembl
- protein serine/threonine kinase activity Source: UniProtKB
- ribosome binding Source: Ensembl
- RNA polymerase III type 1 promoter DNA binding Source: UniProtKB
- RNA polymerase III type 2 promoter DNA binding Source: UniProtKB
- RNA polymerase III type 3 promoter DNA binding Source: UniProtKB
- TFIIIC-class transcription factor binding Source: UniProtKB
GO – Biological processi
- ‘de novo’ pyrimidine nucleobase biosynthetic process Source: Ensembl
- anoikis Source: ParkinsonsUK-UCL
- brain development Source: Ensembl
- cardiac muscle cell development Source: Ensembl
- cardiac muscle contraction Source: Ensembl
- cell aging Source: Ensembl
- cell cycle arrest Source: Reactome
- cell growth Source: UniProtKB
- cellular response to amino acid starvation Source: CAFA
- cellular response to amino acid stimulus Source: CAFA
- cellular response to hypoxia Source: UniProtKB
- cellular response to leucine Source: CAFA
- cellular response to leucine starvation Source: CAFA
- cellular response to nutrient levels Source: UniProtKB
- energy reserve metabolic process Source: Ensembl
- germ cell development Source: Ensembl
- growth Source: UniProtKB
- heart morphogenesis Source: Ensembl
- heart valve morphogenesis Source: Ensembl
- long-term memory Source: Ensembl
- macroautophagy Source: Reactome
- maternal process involved in female pregnancy Source: Ensembl
- mRNA stabilization Source: Ensembl
- multicellular organism growth Source: Ensembl
- negative regulation of autophagy Source: CAFA
- negative regulation of cell size Source: Ensembl
- negative regulation of cholangiocyte apoptotic process Source: Ensembl
- negative regulation of iodide transmembrane transport Source: Ensembl
- negative regulation of macroautophagy Source: MGI
- negative regulation of muscle atrophy Source: Ensembl
- negative regulation of NFAT protein import into nucleus Source: Ensembl
- negative regulation of protein phosphorylation Source: Ensembl
- negative regulation of protein ubiquitination Source: Ensembl
- peptidyl-serine phosphorylation Source: UniProtKB
- peptidyl-threonine phosphorylation Source: Ensembl
- phosphatidylinositol-mediated signaling Source: Reactome
- phosphorylation Source: UniProtKB
- positive regulation of actin filament polymerization Source: Ensembl
- positive regulation of cell growth involved in cardiac muscle cell development Source: Ensembl
- positive regulation of cholangiocyte proliferation Source: Ensembl
- positive regulation of dendritic spine development Source: Ensembl
- positive regulation of eating behavior Source: Ensembl
- positive regulation of endothelial cell proliferation Source: Ensembl
- positive regulation of lipid biosynthetic process Source: UniProtKB
- positive regulation of myotube differentiation Source: Ensembl
- positive regulation of neuron death Source: Ensembl
- positive regulation of neuron maturation Source: Ensembl
- positive regulation of nitric oxide biosynthetic process Source: Ensembl
- positive regulation of oligodendrocyte differentiation Source: Ensembl
- positive regulation of peptidyl-tyrosine phosphorylation Source: Ensembl
- positive regulation of protein kinase B signaling Source: Ensembl
- positive regulation of protein phosphorylation Source: UniProtKB
- positive regulation of sensory perception of pain Source: Ensembl
- positive regulation of skeletal muscle hypertrophy Source: Ensembl
- positive regulation of smooth muscle cell proliferation Source: Ensembl
- positive regulation of stress fiber assembly Source: Ensembl
- positive regulation of transcription from RNA polymerase III promoter Source: UniProtKB
- positive regulation of transcription of nuclear large rRNA transcript from RNA polymerase I promoter Source: UniProtKB
- positive regulation of translation Source: UniProtKB
- positive regulation of wound healing, spreading of epidermal cells Source: BHF-UCL
- post-embryonic development Source: Ensembl
- protein autophosphorylation Source: MGI
- protein catabolic process Source: UniProtKB
- protein phosphorylation Source: UniProtKB
- regulation of actin cytoskeleton organization Source: UniProtKB
- regulation of brown fat cell differentiation Source: Ensembl
- regulation of carbohydrate utilization Source: Ensembl
- regulation of cell size Source: CAFA
- regulation of cellular response to heat Source: Reactome
- regulation of fatty acid beta-oxidation Source: Ensembl
- regulation of glycogen biosynthetic process Source: Ensembl
- regulation of GTPase activity Source: Ensembl
- regulation of membrane permeability Source: Ensembl
- regulation of myelination Source: Ensembl
- regulation of osteoclast differentiation Source: UniProtKB
- regulation of protein kinase activity Source: Ensembl
- regulation of response to food Source: Ensembl
- response to amino acid Source: UniProtKB
- response to cocaine Source: Ensembl
- response to insulin Source: Ensembl
- response to morphine Source: Ensembl
- response to nutrient Source: UniProtKB
- response to stress Source: UniProtKB
- ruffle organization Source: Ensembl
- signal transduction Source: UniProtKB
- social behavior Source: Ensembl
- spinal cord development Source: Ensembl
- T cell costimulation Source: Reactome
- TORC1 signaling Source: WormBase
- TOR signaling Source: UniProtKB
- visual learning Source: Ensembl
- voluntary musculoskeletal movement Source: Ensembl
- wound healing Source: Ensembl