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 [1]. 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!


[1] 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

From wiki

DNA damage appears to be the primary underlying cause of cancer,[8][9] and deficiencies in DNA repair genes likely underlie many forms of cancer.[10][11] 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.[12][13] 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.[14] They were also found in 10% of breast and pancreatic cancers.[15]

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.[16]

DNA-PKcs expression was reduced by 23% to 57% in six cancers as indicated in the table.

Frequency of reduced expression of DNA-PKcs in sporadic cancers

Cancer Frequency of reduction in cancer Ref.
Breast cancer 57% [17]
Prostate cancer 51% [18]
Cervical carcinoma 32% [19]
Nasopharyngeal carcinoma 30% [20]
Epithelial ovarian cancer 29% [21]
Gastric cancer 23% [22]

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.[23] But miR-101 is more often decreased in cancers, rather than increased.[24][25]

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.[26] The let-7a microRNA normally represses the HMGA2 gene.[27][28]

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.[29] 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.[30] After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma tissues.[31]

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).[32] 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.[33](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”,[33] though it would be at the expense of the patient.

As indicated in a table listing 12 types of cancer reported in 20 publications,[33] 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.


Non-homologous end joining (NHEJ) is the principal DNA repair process used by mammalian somatic cells to cope with double-strand breaks that continually occur in the genome.

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.[34][35]

These findings suggest that failure to efficiently repair DNA double-strand breaks results in premature aging, consistent with the DNA damage theory of aging. (See also Bernstein et al.[36])


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.

MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E).
  • 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.
Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at ‘Ser-473’ of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at ‘Ser-422’. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity).

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

  • 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).
On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity.
  • 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

GO – Biological processi