20 October 2014

Genetics of aging: results of the conference

Report on the conference "Molecular Genetics of Aging" in Cold Spring Harbor

Nastya Shubina for LJ Mikhail Batin

From September 29 to October 3, a conference "Molecular genetics of aging" was held at the Cold Spring Harbor Laboratory, located near New York. The conference was organized by Vera Gorbunova from the University of Rochester, Malen Hansen from the Stanford-Burnham Medical Research Institute and David Sinclair from Harvard Medical School. The conference was extremely eventful: reports were delivered from 9 am to 11 pm with short breaks for coffee break/lunch. The organizers tried to present to the audience an exhaustive picture of modern research in the field of genetics of aging and longevity: short reports of 15 minutes were held within 10 sections devoted to all major areas of research in the field of molecular biology of aging. The organizers almost succeeded in creating an exhaustive picture, the reports were full of extremely interesting, completely new, not yet published data. The only thing missing was generalizations: almost all the reports were devoted only to particular aspects of the genetics of aging, but they did not move on to general theories of aging.

Below are brief summaries of some of the reports that seemed interesting to me.

Section "Longevity genes/Human biology"

The report of Danika Chen (University of California, Berkeley) was devoted to the metabolic regulation of aging of stem cells. Normally, some of the stem cells proliferate, and some are at rest. The transition of cells to a resting state is a protective mechanism that prevents cell death, and is necessary for the normal functioning of the SC. In old age, there is a shift of cells into a proliferative state, which is accompanied by depletion of the SC niches. An important role in the regulation of this transition is played by sirtuins 3 and 7, whose activity depends on the metabolic state of cells. In old age, the content of sirtuins 3 and 7 in the SC decreases. Sirtuin 3 reduces oxidative stress, and knockout of this gene leads to a decrease in the number of SC at rest (reactive oxygen species block the transition of cells from a proliferative state to a resting state). Sirtuin 7 also contributes to an increase in the number of SC at rest. Its knockout leads to a decrease in cell survival. In such cells, mitochondria are more active and apoptosis occurs more often. Lentiviral ex vivo delivery of sirtuin3 or 7 to mesenchymal stem cells of old mice, followed by return to old mice, led to an increase in the number of SC. Thus, an increase in the expression of sirtuins 3 and 7 can be used to prevent the depletion of stem cell niches in old age.

Thomas McKenna (Karolinska University, Sweden) spoke about the role of laminin A in the functioning of adipose tissue and aging. Hutchinson-Guilford premature aging syndrome is most often caused by a mutation in the gene of laminins A and C – proteins of nuclear lamina. The authors studied the expression of laminin A (progerin) in different tissues and found out that progerin is not expressed in neurons, and only a low level of its expression is observed in adipocytes (in 2.7% of cells), in osteocytes (in 8.1% of cells) and only a few osteoblasts. In addition, these mice had no subcutaneous fat at all, their bones were shortened and they had an increased content of leukocytes and inflammatory cytokines in the blood. The authors suggested that progerin leads to DNA damage to certain tissues, which leads to cell senility, the release of inflammatory mediators and systemic inflammation. Which, in turn, leads to the depletion of adipose tissue and inhibition of bone growth. In the future, it is necessary to understand how this leads to the appearance of other symptoms of progeria.

Douglas J. Cutty (Massachusetts Institute of Technology) said that in C.elegans, mutations in the genes of unimportant translation initiation factors EIF3K, EIF3L lead to an increase in life expectancy. Moreover, this is not accompanied by a global change in the level of translation. For the manifestation of this effect, the presence of daf-16 is necessary. It is unclear, however, whether such a mechanism is present in mammalian cells, but if it were, homologues of EIF3K, EIF3L could be targets for life-prolonging therapy.

David B. Lombard (University of Michigan) spoke about the role of SIRT5 in the regulation of mitochondrial respiration and the development of cancer. SIRT5 inhibits CTK, which leads to a decrease in mitochondrial respiration and activation of glycolysis. This predisposes to the development of cancer (cancer cells are characterized by a shift in metabolism towards glycolysis). It is already known that the expression of SIRT5 in melanoma cells is increased by 40%. A SIRT5 knockout prevents the development of melanoma. Thus, suppression of SIRT5 expression can be used for cancer therapy.

Robert Schmuckler-Rees (University of Arkansas) spoke about the use of C.elegans as a model of neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.

In such a model, 5 genes involved in the pathogenesis of Huntington's disease were identified by switching off various genes using RNA interference, and the most powerful was the shutdown of the CRAM-1 gene. This led to a decrease in the formation of aggregates by almost 2 times, a later development of paralysis, etc.

Inhibition of the CRAM-1 gene also leads to a slight increase in life expectancy (average life expectancy – by 11%, median – by 19%). In addition, there is a decrease in fertility. CRAM-1 is a primitive chaperone that has positive effects on reproduction, but has negative effects with aging.

The report by Changhan Lee (University of Southern California) is devoted to the role of mitochondrial peptides in aging. Thus, several peptides (humanin, MOTS-c) have been identified, the expression of which decreases with age. They presumably have signaling functions, regulate homeostasis, and play a role in the "communication" of mitochondria with the host cell. Humanin expression is suppressed by IGF-1. MOTS-c is an important regulator of glucose metabolism and insulin sensitivity. MOTS-c treatment of mice activates AMPK in skeletal muscles and prevents the emergence of insulin resistance. Thus, these peptides can be targets of anti-aging therapy.

Seungjin Riu (Albert Einstein College of Medicine) spoke about the association of polymorphisms in the genes responsible for cognitive functions with longevity. 568 candidate genes (involved in cognitive function) were tested. It was found that centenarians have many rare polymorphisms in the genes of the PKA/PKC pathway. A decrease in PKC expression in drosophila prolongs its life (it is known that suppression of PKC expression leads to a decrease in the expression of transcription factor NF-kB).

Haim Kohen (Bar-Ilan University, Israel) made a report on the effect of SIRT6 on life expectancy. SIRT6 is responsible for DNA repair, retrotransposon stabilization, regulation of the NF-kB transcription factor pathway, nutrition restriction, and the Warburg effect. The authors showed that overexpression of SIRT6 leads to an increase in life expectancy (statistically significant, but not very large) in mice of both sexes, and also contributes to the improvement of many age indicators. An increase in SIRT6 expression leads to AMPK activation.Mice with overexpression of SIRT6 are thinner, their cholesterol and triacylglycerol levels are reduced.

Sergiy Libert (Cornell University) spoke about the role of SIRT6 in the development of Alzheimer's disease. Overexpression of SIRT6 makes cells more sensitive to apoptosis, and also leads to an increase in the synthesis of inflammatory cytokines and stimulates inflammation. In a mouse model of Parkinson's disease, it was shown that the SIRT6 knockout has a neuroprotective effect, in such mice motor activity increased and anxiety decreased. Thus, inhibition of SIRT6 may be effective in preventing the development of neurodegenerative diseases.

Section: "DNA repair/cellular aging"

Laura Niedernhofer (Scripps Research Institute, Florida) spoke about a study in which she showed that DNA damage caused by reactive oxygen species leads to cellular aging. The studies were conducted on mice with premature aging syndrome caused by a mutation in the gene
ERCC1-XPF endonuclease, which is involved in 3 types of DNA damage repair. Such mice age 6 times faster than normal mice, they accumulate oxidative DNA damage 5-6 times faster, aging cells, as well as mutant mice have more inflammatory cytokines, and their cells are characterized by a hypermetabolic phenotype. The changes that occur with mutant mice are similar to the changes with normal mice in old age. Treatment of mutant mice with an agent that reduces the amount of reactive oxygen species in mitochondria leads to a decrease in the number of DNA and senescent cell damage. The authors conclude that DNA damage and cell decrepitude trigger systemic effects of aging.

Marco de Cecco (Brown University) made a report on the activity of transposons in aging. Using a model of human fibroblasts in a state of replicative aging, it was shown that chromatin rearrangements occur with age, which lead to an increase in the availability of repeating elements (in particular, retrotransposons L1 (22% of all repeating elements) and Alu (18%)) for transcription enzymes, and an increase in their expression.

Interestingly, in mice, not only activity increases with age, but also the number of transposons. Among the huge number of transposons in the genome, only about 150 are functionally active. However, most of them are expressed basally and only a few are expressed specifically in aging cells. Moreover, despite the activation of transposon transcription in old age, there are no global changes in the methylation of promoters. The role of transposons in the regulation of aging, among other things, it is known that they can trigger an autoimmune response, which leads to cell aging.

A report by Morten Scheibi-Knudsen (National Institutes of Health) was devoted to the effect of a high-fat diet on the rate of aging in the case of Coccain syndrome. This disease is caused by a mutation in the gene of the DNA repair enzyme (CSA or CSB) and leads to premature aging. The use of fatty foods by mice with Coccain syndrome led to improvements in the metabolism, transcriptome and behavior of such mice. The intake of fatty foods is accompanied by an increase in the level of beta-hydroxybutyrate. In Coccain syndrome, PARP (Poly (ADP-ribose) is activated-polymerase – involved in DNA repair), which in turn reduces the activity of SIRT1 (since both enzymes require the same substrate – NAD+) and leads to disruption of mitochondrial functions.

Thus, beta-hydroxybutyrate, NAD+, or inhibition of PARP due to activation of SIRT1 can lead to a slowdown in premature aging in Coccain syndrome.

Celia Cuigiano (Center for Free Radical Research and Biomedical Research, Uruguay) said that the suppression of lipid synthesis (on the model of human fibroblasts) leads to activation of the response to DNA damage, an increase in the content of reactive oxygen species and cellular aging.

The report by Patrick Maxwell (Rensselaer Polytechnic Institute) was devoted to age-dependent changes in retrotransposon activity in yeast. In both humans and yeast, activation of retrotransposons leads to an increase in the number of reactive oxygen species and chromosomal rearrangements.
In addition, it is interesting that in the yeast population, with age, there is a surge in chromosomal rearrangements (as well as insertions of transposons), and then (at the end of the population's life) a decline. This may be due to the elimination of individuals with severe genome disorders from the population.

Wenge Lee (Albert Einstein College of Medicine) spoke about the features of the accumulation of mutations with age. A 60-day-old fruit fly has 4 times more mutations than a 5-day-old one. Most of the mutations in somatic cells were GC-AT substitutions (caused, most often, by reactive oxygen species). Interestingly, in the germ cells, different types of substitutions were variously likely. Thus, the ratio of missense mutations and nonsense mutations was low, which indicated a strict selection of germ cells.

Studies of the genomes of old fruit flies have shown that somatic mutations are most often found in exons and non-coding regulatory regions of genomes.

The report of Nadia Ring (International Center for Genetic Engineering and Biotechnology) was devoted to the role of microRNAs in the regulation of cellular aging. They studied all 879 human microRNAs and found out that 20 microRNAs induce the proliferation of old cells in the absence of growth factors. Interestingly, the culture medium in which cells transfected with the corresponding microRNAs were grown was also able to induce the proliferation of old (senescent) fibroblasts. Thus, microRNAs can be used to combat cellular aging.

Section "Comparative Biology"

Andrey Seluyanov (University of Rochester) made a report on the mechanisms of longevity of a naked digger – a rodent that lives 10 times longer than a house mouse. The naked digger synthesizes a long form of hyaluronic acid, which prevents the association of cancer cells and prevents tumors from developing. In this regard, naked diggers do not suffer from cancer. In addition, the hematopoietic stem cells of the naked digger are much more resistant to stress, there are more of them than in a mouse and their renewal is much slower.

Interestingly, the longer a rodent lives, the more difficult it is to induce pluripotency of its stem cells. A possible explanation is that such rodents have a much more stable epigenome.

Siao Tian (University of Rochester) investigated the correlation of the efficiency of double-chain break repair and excision repair of nucleotides with life expectancy in different rodents (18 species). It turned out that the efficiency of repair of double–stranded breaks correlates with the maximum lifespan, and excision repair of nucleotides - only with the circadian rhythm (dynamics of exposure to UV radiation). The mechanisms of repair of double-strand breaks include homologous recombination and non-homologous reunion of the ends. It has been shown that RAD51 (the most important factor involved in homologous recombination) in long-lived species is transported faster to the nucleus for repair of 2-strand breaks. So, in humans, its transport takes 10 times less time than in a mouse. In addition, overexpression of RAD51 in fibroblasts of short-lived animals stimulates homologous recombination more strongly than in cells of long-lived animals, which suggests that the transport of RAD51 to the nucleus is the limiting stage for homologous recombination.

Stijn Mouton (Medical Center of the University of Groningen, the Netherlands) spoke about the use of the flatworm Macrostomum lignano as a model object of aging genetics. For quite a long time, this worm has been used as a model for regeneration/rejuvenation. He has a population of somatic stem cells and if you cut such a worm, complete regeneration will occur in about 3 weeks. Studies were conducted in which the life expectancy of the worm, which was repeatedly cut and regenerated, and the control worm were compared. They found that the control worm lived longer. Interestingly, in this case, regeneration did not contribute to rejuvenation, but, on the contrary, accelerated aging.

Vadim Gladyshev (Harvard Medical School) spoke about the use of comparative genomics methods to study aging. The genomes of such long-lived species as the Damar sandworm, naked digger, and Brandt's moth were studied. The naked digger had UPC1, p16, melatonin, and telomerase genes among the genes that could mediate its longevity. Brandt's moth (which has lived for more than 40 years) has GHR, IGF1R. Mutations in the GHR growth hormone receptor gene lead to the fact that Brandt's moth develops a phenotype similar to the dwarf phenotype in mice with a similar mutation.

Itamar Harel (Stanford University) spoke about the short-lived fish Nothobranchius furzeri, which is convenient to use as a model object of aging genetics. The lifetime of the fish is 4-6 months. A fish with a telomerase gene knockout has already been created, which can be a model of diseases associated with disorders of telomerase activity in humans.

The report by Petteri Ilmonen (University of Turku) is devoted to the effects of different telomere lengths on life expectancy and other indicators of mice. In humans, shortening of telomeres leads to an increased risk of cardiovascular diseases, cancer, etc. Mice with insufficient telomerase activity age faster, have reduced fertility, immune system disorders, and impaired tissue renewal.

The researchers took wild-type mice (not laboratory mice) and began to select mice for telomere length. As a result, mice with shortened telomeres and with longer telomeres were obtained. Interestingly, both lived longer than the original mice. Moreover, mice with short telomeres lived the longest (although the differences from mice with long telomeres were unreliable). It is also interesting that in laboratory mice, long telomeres cause cancer.

Matthias Ziem (University College London) spoke about the creation of a database of the life expectancy of various animals exposed to various influences.

Homeostasis Section

Toren Finkel (National Institutes of Health) spoke about the effects of reduced expression of the mTOR gene in mice. In such mice, insertion into the region of the mTOR locus occurred, which led to the expression of this gene being 25% of the basal level. The median life expectancy of these mice was about 20% longer, they were smaller in size, but there was no change in metabolic parameters (food intake, glucose homeostasis, metabolic rate). In addition, these mice showed a decrease in biomarkers of aging, as well as the preservation of the functions of many, but not all systems. Interestingly, these mice were more likely to develop infections, and there was also an increased rate of bone loss.

The report by Ara Hwang (Pohang University of Science and Technology, South Korea) talks about how reactive oxygen species increase the lifespan of C.elegans by activating HIF-1. HIF-1 is activated in response to reactive oxygen species (formed by mitochondria) and further increases their content by a positive feedback mechanism. Another protein that is activated in response to reactive oxygen species – AMPK, on the contrary, reduces the content of reactive oxygen species and induces longevity. As a result, when exposed to mitochondrial reactive oxygen species, C.elegans live longer.

A report by Jun Lee (from the Laboratory of Research on Biological Mechanisms of Aging by Paula F. Glenn) is dedicated to the role of NAD+ and proteins that are activated by NAD+ during aging. NAD+ is a substrate or cosubstrate of PARP (poly(ADP-ribose)-polymerases, PARP1 – participates in DNA repair) and sirtuins, in addition, it regulates a number of biological processes, such as gene expression, chromatin remodeling and mitochondrial functioning. With age, there is a decrease in the content of NAD+ in various cellular compartments. In response to DNA damage due to the work of PARP, NAD+ reserves in the cell are also very quickly depleted, which leads to cell death.

The gene 1 (DBC1) deleted in breast cancer binds PARP1, which leads to the accumulation of DNA damage. NAD+ interferes with this interaction, however, with aging, its content decreases and the interaction of DBC1 with PARP1 increases. However, if old mice are exposed to the NAD+ – NMN precursor, DNA repair improves.

Brian Wilson (Institute of Genetic Medicine, Newcastle University) he spoke about the role of Golgi complex dysfunction in the development of premature aging. Coccain syndrome (one of the syndromes of premature aging) is characterized by a mutation in the genes of DNA repair proteins CSA or CSB. Normally, CSA and CSB are nuclear proteins, but mutations in these genes can cause them to accumulate in the Golgi complex, which leads to disruption of its work (improper localization of enzymes occurs, violation of glycoprotein modifications). Interestingly, in the case of a complete knockout of the CSB protein, violations of the Golgi complex disappear. Since a number of pathologies associated with impaired transport of the Golgi complex or impaired glycosylation are observed in Coccain syndrome, the authors suggest that it is precisely violations of the Golgi complex that can lead to premature aging.

Andrew Dilin (UC Berkeley) spoke about the possibility of increasing the lifespan of C.elegans by affecting mitochondria. Mitochondrial stress in the nervous tissue leads to the transmission of signals from the mitochondria to the nucleus. The expression of a number of stress response genes under the regulation of UBL-5 and DVE-1 is triggered in the nucleus. In addition, cells begin to produce specific signals "mitokines", which can be transmitted to distant cells (in this case, intestinal cells), in which a response to mitochondrial stress is triggered, which in turn leads to an increase in the lifespan of C.elegans.

Anthony Roakes (University of California San Francisco) He said that with the arrest of development (caused by lack of food) at the L1 stage, the larva of C.elegans begins to demonstrate the phenotype of aging. Interestingly, after feeding in such a worm, almost all markers of aging disappear (except protein aggregates). In such worms, the life expectancy does not change. It turned out that the rejuvenation of the worm is mediated by a non-canonical IRE-1 dependent, endoplasmic reticulum-mediated response to stress.

Portal "Eternal youth" http://vechnayamolodost.ru 20.10.2014

Found a typo? Select it and press ctrl + enter Print version