Recent Research on Aging-Related Genes and Proteins

Below find links to a few recent papers relating to the genetics and epigenetics of aging. Aging is a byproduct of the normal operation of cellular metabolism, due to damage generated and not repaired. Many genes will have some impact on the progression of aging because they govern the operation of metabolism and thus influence the pace at which unrepaired damage accumulates. As time progresses and the damage of aging builds up, cells react to that damage with changes to the epigenetic regulation of the production of proteins. Thus old individuals have more of some proteins and less of others in circulation and present in various tissues, changing the way in which cells and tissues function. Some of this is compensation, and aging would be faster and worse without it, but some of it is just more dysfunction piled on top of that caused directly by damage to cells and their component parts.

Much of the aging research field is involved in cataloging: firstly finding genes associated with the pace of aging by dint of altering them one by one in short-lived and well-characterized species such as yeast or nematode worms, and secondly finding genes whose output of proteins changes with age by precisely measuring the molecules present blood and other bodily fluids at various different ages. Gathering information about how exactly aging progresses at the detail level still has a higher priority for most researchers in comparison to moving beyond that to try to treat aging.

There are some necessary tools that will emerge from cataloging efforts, however. One is a good biomarker of biological age, a measurement that must be cheap and easy to carry out given simple patient samples such as skin or saliva, and comprehensive enough to pick up the beneficial effects of a partial rejuvenation therapy soon after it is applied. For rejuvenation based on repair of cell and tissue damage after the SENS model, researchers can always identify how much of the specific form of damage has been repaired by their treatment, but there is still the need to link that to some reliable and accepted measure of overall biological age for the organism as a whole. Without that biomarker the only way to prove that rejuvenation has happened is to wait and see: run the life span study, which even in mice requires years and millions of dollars, never mind in longer-lived mammals. The need for life span studies as proof is a real drag on the pace of progress.

Identification of ageing-associated naturally occurring peptides in human urine

In a first small scale study, we investigated the urinary proteome in a cohort of 324 healthy individuals between 2 to 73 years of age showing the feasibility to obtain high resolution molecular information from readily available body fluids such as urine. Meanwhile, we have accumulated multiple high-resolution urine peptidomics datasets that enable the investigation of ageing-associated changes in a large cohort. In the present study, we therefore investigated the unique urinary proteome profiles of 11,560 individuals in an attempt to identify specific ageing-associated alterations and investigate pathological derailment of normal ageing. This showed that perturbations in collagen homeostasis, trafficking of toll-like receptors and endosomal pathways were associated to healthy ageing, while degradation of insulin-like growth factor-binding proteins was uniquely identified in pathological ageing.

Length of paternal lifespan is manifested in the DNA methylome of their nonagenarian progeny

The heritability of lifespan (age at death) has been estimated to be approximately 20-30%, and it has been shown to increase with advancing age. Healthy aging is also heritable, and the offspring of long-lived parents show delayed onset of aging-associated diseases. Much of the research studying the heritability of lifespan has focused on extreme age (nonagenarians, centenarians, supercentenarians), but recently it has been shown that every decade of parental age after the age of 65 reduces the mortality and incidence of cancer of their offspring. Even though the heritability of the lifespan is acknowledged, only one genomic locus (on chromosome 3) and a few genetic variants, such as in APOE and FOXO3, have consistently been shown to be associated with longevity. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan.

We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5. In addition, the level of methylation in three Notch-genes (NOTCH1, NOTCH3 and NOTCH4) was also associated with paternal lifespan.

The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan

The heat-shock protein 70 (Hsp70) acts as a cellular defense mechanism its expression being induced under stressful conditions. Aging has been related to an impairment in this induction. However, an extended longevity has been associated with its increased expression. According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the age-related alterations of body cells. Since oxidation and inflammation are interlinked processes, and Hsp70 has been shown to confer protection against the harmful effects of oxidative stress as well as modulating the inflammatory status, it could play a role as a regulator of the rate of aging.

Mapping the Genes that Increase Lifespan

Following an exhaustive, ten-year effort, scientists 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. "This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is. It also sets up a framework to define the entire network that influences aging in this organism." Researchers began the painstaking process by 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. 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. The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes."

Comments

It is fascinating to see discussion on the various paradigms such as genetics, proteomics, transcriptomcis and clinical associated to Ageing. Cancer and Ageing situations seems to be paradoxical.

However, fighting ageing based on genetics has been an important finding made by scientists at Insilco Inc: http://www.oncologybiomarkers.com/2015/05/insilico-medicine-superpharman.html

Posted by: Ankit at October 11th, 2015 11:47 PM

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