FOXO3, a gene linked to intelligence and involved in insulin signalling that might trigger apoptosis


Genes linked to intelligence

Researchers discovered that the genes that were the strongest linked to intelligence are ones involved in pathways that play a part in the regulation of the nervous system’s development and apoptosis (a normal form of cell death that is needed in development). The most significant SNP was found within FOXO3, a gene involved in insulin signalling that might trigger apoptosis. The strongest associated gene was CSE1L, a gene involved in apoptosis and cell proliferation.

Does this all mean that intelligence in humans depends on the molecular mechanisms that support the development and preservation of the nervous system throughout an person’s lifespan? It’s possible.

And is it possible to explain intelligence through genetics? This paper suggests it is. Nevertheless, it might be warranted to consider that intelligence is a very complex trait and even if genetics did play a role, environmental factors such as education, healthy living, access to higher education, exposure to stimulating circumstances or environments might play an equally or even stronger role in nurturing and shaping intelligence.

It is also worth considering that the meaning of “intelligence” rather falls within a grey area. There might be different types of intelligence or even intelligence might be interpreted differently: in which category would for example a genius physicist – unable to remember their way home (Albert Einstein) – fall? Selective intelligence? Mozart nearly failed his admission tests to Philharmonic Academy in Bologna because his genius was too wide and innovative to be assessed by rigid tests. Is that another form of selective intelligence? And if so, what’s the genetic basis of this kind of intelligence?

Studies like this are extremely interesting and they do show we are starting to scratch the surface of what the biological basis of intelligence really is.

This article was originally published on The Conversation. Read the original article.

About FOX0

What are they? FOXO proteins are a subgroup of the Forkhead family of transcription factors. This family is characterized by a conserved DNA-binding domain (the ‘Forkhead box’, or FOX) and comprises more than 100 members in humans, classified from FOXA to FOXR on the basis of sequence similarity. These proteins participate in very diverse functions: for example, FOXE3 is necessary for proper eye development, while FOXP2 plays a role in language acquisition. Members of class ‘O’ share the characteristic of being regulated by the insulin/PI3K/Akt signaling pathway. How did this family get named ‘Forkhead’? Forkhead, the founding member of the entire family (now classified as FOXA), was originally identified in Drosophila as a gene whose mutation resulted in ectopic head structures that looked like a fork.

Forkhead proteins are also sometimes referred to as ‘winged helix’ proteins because X-ray crystallography revealed that the DNA-binding domain features a 3D structure with three α-helices flanked by two characteristic loops that resemble butterfly wings.

How many FOXOs are there? In invertebrates, there is only one FOXO gene, termed daf-16 in the worm and dFOXO in the fly. In mammals, there are four FOXO genes, FOXO1, 3, 4, and 6. Hey, what about FOXO2 and FOXO5? FOXO2 is identical to FOXO3 (a.k.a. FOXO3a, as opposed to FOXO3b, a pseudogene). FOXO5 is the fish ortholog of FOXO3. FOX hunting…

FOXO genes were first identified in humans because three family members (1, 3, and 4) were found at chromosomal translocations in rhabdomyosarcomas and acute myeloid leukemias. Just after FOXO factors were identified in human tumor cells, the crucial role of DAF-16 in organismal longevity was discovered in worms.

DAF-16 activity was shown to be negatively regulated by the insulin/PI3K/Akt signaling pathway. Subsequent experiments in mammalian cells showed that mammalian FOXO proteins were directly phosphorylated and inhibited by Akt in response to insulin/ growth factor stimulation. Thus, FOXO factors are evolutionarily conserved mediators of insulin and growth factor signaling.

Why are they important? FOXO transcription factors are at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell-cycle progression, and oxidativestress resistance (Figure 1). For example, FOXO factors can initiate apoptosis by activating transcription of FasL, the ligand for the Fas-dependent celldeath pathway, and by activating the pro-apoptotic Bcl-2 family member Bim. Alternatively, FOXO factors can promote cellcycle arrest; for example, FOXO factors upregulate the cell-cycle inhibitor p27kip1 to induce G1 arrest or GADD45 to induce G2 arrest.

FOXO factors are also involved in stress resistance via upregulation of catalase and MnSOD, two enzymes involved in the detoxification of reactive oxygen species. Additionally, FOXO factors facilitate the repair of damaged DNA by upregulating genes, such as GADD45 and DDB1. Other FOXO target genes have been shown to play a role in glucose metabolism, cellular differentiation, muscle atrophy, and even energy homeostasis.

Is there a connection between FOXO and cancer?

Because FOXO proteins were originally identified in human tumors, and because they play an important role in cell-cycle arrest, DNA repair, and apoptosis — cell functions that go awry in cancer — the FOXO family is thought to coordinate the balance between longevity and tumor suppression. Consistent with this idea, in certain breast cancers, FOXO3 is sequestered in the cytoplasm and inactivated. Expression of active forms of FOXO in tumor cells prevents tumor growth in vivo. Additionally, protein partners of FOXO, such as p53 and SMAD transcription factors, are tumor suppressors. Investigating the ensemble of FOXO protein partners will provide insight into the connection between aging and cancer.

Muscle Enzyme Explains Weight Gain in Middle Age, Cancer and Aging

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

Yoga and behavioral memory interventions for the aging brain

Yoga and behavioral memory interventions to prevent age-related cognitive decline

A study examined changes in brain metabolites and structure among individuals undergoing memory training and yogic meditation. We demonstrated that memory training over 3 months is associated with decreased choline levels in bilateral hippocampus and increased gray-matter volume in dACC, suggesting that behavioral interventions like MET may ameliorate markers of brain aging. These effects are somewhat modest, and would benefit from independent validation in larger samples and perhaps over longer-duration interventions. However, these findings suggest that engaging in cognitive activities and mind-body practices may affect the brain in positive ways, and may be combined as part of a multi-faceted approach to encourage healthy aging.

Behavioral memory training is also popular, based on the notion that cognition is plastic in older age (Acevedo and Loewenstein, 2007; Eyre et al., 2016). For example, traditional memory training interventions that teach mnemonic techniques involving verbal association and visual imagery and practical strategies have been shown to boost cognitive performance, memory, and quality of life in healthy older adults (Verhaeghen et al., 1992; Jean et al., 2010). Given the growing popularity of online “Brain Training” programs, clearer understanding of behavioral memory training programs already demonstrated to be effective in the clinic is needed.

In recent years, mind-body therapies have also been studied as potential preventive measures for MCI (Grossman et al., 2004). By simultaneously targeting multiple physiological and cognitive processes, as well as their dynamic integration, meditation may offer a more efficient alternative to other behavioral interventions. Indeed, some studies indicate that senior meditators have better memory, perceptual speed, attention and executive functioning compared with non-meditators (Prakash et al., 2012), though results are mixed (Chiesa et al., 2011; Goyal et al., 2014). A combination of Kirtan Kriya (KK) meditation and Kundalini Yoga (KY), as used as an intervention in the current study, is specifically shown to affect physical and mental health outcomes (Shannahoff-Khalsa, 2004; Krisanaprakornkit et al., 2006), including older adults with memory complaints (Moss et al., 2012). Like other forms of mind-body practice, KY and KK have been demonstrated to benefit cognitive function, depressed mood and anxiety, sleep and coping (Black et al., 2013; Lavretsky et al., 2013), including older adults with cognitive impairments (Newberg et al., 2010).

Role of Anterior Cingulate Cortex in Cognitive Aging

In our study, we provide novel evidence that a behavioral memory intervention (MET) can modestly increase cortical gray matter in dACC, a region of the brain linked to multiple key cognitive functions, such as error detection (Gehring et al., 1993), and executive processing (Carter et al., 2000). Gray-matter volume has been demonstrated to decrease with age in the ACC in both cross-sectional (Sowell et al., 2003) and longitudinal studies (Resnick et al., 2003). Correspondingly, age is negatively correlated with blood flow in dorsal and rostral ACC regions (Vaidya et al., 2007). Seniors who engage more in cognitive games and puzzles in their daily lives also tend to have greater ACC gray matter volume (Schultz et al., 2015), which is consistent with our results and raises the possibility that engaging in cognitive-behavioral games or training could prevent age-related structural atrophy in this region. Indeed, a recent study indicated a trend towards increased rostral ACC thickness in seniors after MET; however, this effect did not survive a stringent validation analysis (Engvig et al., 2010). Although our effects are modest, they do indicate that participating in effective behavioral interventions may help to ameliorate age-related brain changes associated with poor memory and cognitive performance.

Yoga and the Aging Brain

Structural plasticity in the dACC and hippocampus has also been associated with yoga practice in previous studies; however, we did not find evidence of gray-matter volume changes in dACC or hippocampus after our 12-week yoga intervention. Yoga has been linked to anatomical changes in frontal cortex (Baijal and Srinivasan, 2010; Froeliger et al., 2012; Villemure et al., 2014; Desai et al., 2015), anterior cingulate cortex (ACC) and insula (Nakata et al., 2014; Villemure et al., 2014, 2015), and the hippocampus (Froeliger et al., 2012; Villemure et al., 2015). However, many of these studies compare the brains of practiced yogis with several months or years of experience to yoga-naive controls (Froeliger et al., 2012); perhaps the relatively shorter length of training in the current study (12 weeks) was less conducive to detecting structural plasticity associated with our yoga intervention. In this same cohort, we have already demonstrated that memory improvements after yoga and MET may induce functional plasticity in similar brain regions (Eyre et al., 2016).

Natural communication breakdown in aging

A naturally produced compound rewinds aspects of age-related demise in mice.

Researchers have discovered a cause of aging in mammals that may be reversible.

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

This image shows and labels the mitochondria.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The findings are published Dec. 19 in Cell.

Communication breakdown

Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

The is the SIRT1 protein.

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

“This was at odds with what the literature suggested,” said Gomes.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell’s ability to make energy, and signs of aging and disease become apparent.

“This particular component of the aging process had never before been described,” said Gomes.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.

This is a diagram which shows what happens when the nucleus breaks down.

Cancer connection

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.

One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.

“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We’re starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”

“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.

The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.

Notes about this neurogenetics and aging research

The Sinclair lab is funded by the National Institute on Aging (NIA/NIH), the Glenn Foundation for Medical Research, the Juvenile Diabetes Research Foundation, the United Mitochondrial Disease Foundation and a gift from the Schulak family.

Written by David Cameron
Contact: David Cameron – Harvard University
Source: Harvard University press release
Image Source: The images are credited to Ana Gomes and are adapted from the Harvard press release.
Original Research: Abstract for “Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging” by Ana P. Gomes, Nathan L. Price, Alvin J.Y. Ling, Javid J. Moslehi, Magdalene K. Montgomery, Luis Rajman, James P. White, João S. Teodoro, Christiane D. Wrann, Basil P. Hubbard, Evi M. Mercken, Carlos M. Palmeira, Rafael de Cabo, Anabela P. Rolo, Nigel Turner, Eric L. Bell, and David A. Sinclair in Cell. Published online December 19 2013 doi:10.1016/j.cell.2013.11.037

Here are four foods that are good sources of resveratrol

Red Grapes

Grapes don’t have to be fermented to contain this antioxidant. It’s actually found in the skin of red grapes along with other nutrients, such as minerals manganese and potassium and vitamins K, C and B1.

Peanut Butter

Peanut butter is great for dressing up apples and celery, but it also contains some resveratrol (up to .13 mg per cup). Peanut butter is a great source of niacin and manganese.

Dark Chocolate

In dark chocolate, resveratrol blends nicely with other antioxidants and also minerals, such as iron, copper and manganese. Who doesn’t like chocolate?


Blueberries don’t have quite as much resveratrol as grapes, but they are also a great source of other antioxidants, dietary fiber, vitamins C and K and manganese.


Nicotinamide adenine dinucleotide (NADH) supplements can be used by people struggling with clinical depression, those affected by Alzheimer’s disease and Parkinson’s disease as well as people with long term chronic fatigue syndrome. The beneficial effects of nicotinamide adenine dinucleotide (NADH) will best be felt after supplementation goes on for some period of time. Each patient may respond to the supplement in a different way.

Some condition specific uses of NADH are discussed below in brief.

Nicotinamide adenine dinucleotide (NADH) facilitates in providing relief from a health condition known as chronic fatigue syndrome.

The nicotinamide adenine dinucleotide (NADH) is primarily found in the foods like fish, all poultry, and cattle, and in yeast containing food products.

Though it may be a little hard to find, NADH supplements can be found in some health food stores.

Nevertheless, it is yet to be ascertained whether the body is able to effectively take up or make use of the NADH obtained from the above mentioned sources. In addition to the sources mentioned above, NADH is also available in the form of a dietary supplement.

Deficiencies and susceptibility

A deficiency of nicotinamide adenine dinucleotide (NADH) can only happen if the diet is deficient in vitamin B3, and except in long term alcoholics, deficiencies of the vitamin B3 is almost unknown in the modern western world.

Missed Connections: Memory Related Brain Activity Loses Cohesion As We Age

Summary: Researchers report groups of brain regions that synchronize their activity during memory tasks become smaller and more numerous as people age.

Source: PLOS.

Groups of brain regions with coordinated activity are consistent for individuals, but shrink with age.

Groups of brain regions that synchronize their activity during memory tasks become smaller and more numerous as people age, according to a study published in PLOS Computational Biology.

Typically, research on brain activity relies on average brain measurements across entire groups of people. In a new study, Elizabeth Davison of Princeton University, New Jersey, and colleagues describe a novel method to characterize and compare the brain dynamics of individual people.

The researchers used functional magnetic resonance imaging (fMRI) to record healthy people’s brain activity during memory tasks, attention tasks, and at rest. For each person, fMRI data was recast as a network composed of brain regions and the connections between them. The scientists then use this network to measure how closely different groups of connections changed together over time.

They found that, regardless of whether a person is using memory, directing attention, or resting, the number of synchronous groups of connections within one brain is consistent for that person. However, between people, these numbers vary dramatically.

Image shows brain scans.

During memory specifically, variations between people are closely linked to age. Younger participants have only a few large synchronous groups that link nearly the entire brain in coordinated activity, while older participants show progressively more and smaller groups of connections, indicating loss of cohesive brain activity–even in the absence of memory impairment.

“This method elegantly captures important differences between individual brains, which are often complex and difficult to describe,” Davison says. “The resulting tools show promise for understanding how different brain characteristics are related to behavior, health, and disease.”

Future work will investigate how to use individual brain signatures to differentiate between healthily aging brains and brains with age-related impairments.


Funding: This work was supported by the David and Lucile Packard Foundation and the Institute for Collaborative Biotechnologies through grant W911NF-09-0001 from the U.S. Army Research Office. KJS was supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1144085. END was supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1656466 and the Francis Robbins Upton Fellowship in Engineering. END and KJS were additionally supported by the Worster Fellowship. DSB acknowledges support from the John D. and Catherine T. MacArthur Foundation, the Army Research Laboratory and the Army Research Office through contract numbers W911NF-10-2-0022 and W911NF-14-1-0679, the National Institute of Mental Health (2-R01-DC- 009209-11), the National Institute of Child Health and Human Development (1R01HD086888-01), the Office of Naval Research, and the National Science Foundation (#BCS-1441502, #BCS-1430087, and #PHY-1554488). The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Source: Elizabeth N. Davison – PLOS
Image Source: image is credited to Davison et al.
Original Research: Full open access research for “Individual Differences in Dynamic Functional Brain Connectivity across the Human Lifespan” by Elizabeth N. Davison, Benjamin O. Turner, Kimberly J. Schlesinger, Michael B. Miller, Scott T. Grafton, Danielle S. Bassett, and Jean M. Carlson in PLOS Computational Biology. Published online November 23 2016 doi:10.1371/journal.pcbi.1005178

PLOS. “Missed Connections: Memory Related Brain Activity Loses Cohesion As We Age.” NeuroscienceNews. NeuroscienceNews, 23 November 2016.


Individual Differences in Dynamic Functional Brain Connectivity across the Human Lifespan

Individual differences in brain functional networks may be related to complex personal identifiers, including health, age, and ability. Dynamic network theory has been used to identify properties of dynamic brain function from fMRI data, but the majority of analyses and findings remain at the level of the group. Here, we apply hypergraph analysis, a method from dynamic network theory, to quantify individual differences in brain functional dynamics. Using a summary metric derived from the hypergraph formalism—hypergraph cardinality—we investigate individual variations in two separate, complementary data sets. The first data set (“multi-task”) consists of 77 individuals engaging in four consecutive cognitive tasks. We observe that hypergraph cardinality exhibits variation across individuals while remaining consistent within individuals between tasks; moreover, the analysis of one of the memory tasks revealed a marginally significant correspondence between hypergraph cardinality and age. This finding motivated a similar analysis of the second data set (“age-memory”), in which 95 individuals, aged 18–75, performed a memory task with a similar structure to the multi-task memory task. With the increased age range in the age-memory data set, the correlation between hypergraph cardinality and age correspondence becomes significant. We discuss these results in the context of the well-known finding linking age with network structure, and suggest that hypergraph analysis should serve as a useful tool in furthering our understanding of the dynamic network structure of the brain.

“Individual Differences in Dynamic Functional Brain Connectivity across the Human Lifespan” by Elizabeth N. Davison, Benjamin O. Turner, Kimberly J. Schlesinger, Michael B. Miller, Scott T. Grafton, Danielle S. Bassett, and Jean M. Carlson in PLOS Computational Biology. Published online November 23 2016 doi:10.1371/journal.pcbi.1005178

Mapping Genes That Increase Lifespan

Comprehensive study finds 238 genes that affect aging in yeast cells.

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

Image shows yeast cells.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”


Other Buck Institute researchers involved in the study include: Mark A. McCormick (first co-author), Mitsuhiro Tsuchiya, Scott Tsuchiyama, Arianna Anies, Juniper K. Pennypacker, Shiena Enerio, Dan Lockshon, Brett Robinson, Ariana A. Rodriguez, Marc K. Ting, and Rachel B. Brem. A full list of authors is included in the paper.

Funding: This research was supported by NIH grants R01AG043080, R01AG025549, R01AG039390 and P30AG013280, as well as NIH training grants T32AG000266, T32AG000057 and T32ES007032 and the Ellison Medical Foundation.

The authors declare no competing financial interests.

Source: Anne Holden – Buck Institute
Image Credit: The image is adapted from the Buck Institute press release
Original Research: Abstract for “A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging” by Brian Kennedy et al. in Cell Metabolism. Published online October 8 2015 doi:10.1016/j.cmet.2015.09.008


A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging

•4,698 deletions tested yields the most comprehensive yeast data set on aging
•Longevity clusters center on known, conserved biological processes
•Enrichment of lifespan-extending C. elegans orthologs suggests conservation
•Genome-wide information uncovered aging pathways such as tRNA transport

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

“Neural mechanisms supporting maladaptive food choices in anorexia nervosa” by Karin Foerde, Joanna E Steinglass, Daphna Shohamy and B Timothy Walsh in Nature Neuroscience. Published online October 12 2015 doi:10.1038/nn.4136