What influence does genetics have on aging?
When biological time runs slowly, which genetic changes increase life expectancy?
Research Report 2016 - Max Planck Institute for Biology of Aging
Aging is plastic
Why we age is a question people have probably always asked themselves. Which internal and external factors contribute to aging and which biological processes are particularly affected by aging? More importantly, which processes define the biology of youth? Is aging preprogrammed or can we influence the course?
Like many biological phenomena, aging processes are the subject of basic research. In numerous organisms, single gene mutations can increase and even more than double life expectancy . This means that aging must be a regulated process and that certain genes have a direct influence on the course of aging. Extreme differences in life expectancy between species can be observed in nature, with life expectancy mostly correlating with body size. But there are certain ones outlier. Mice, for example, live around three years, while bats of the same body weight live around twenty years. Humans are one too outlier. Overall, aging is a plastic process: cells and organs do not have a fixed lifespan. Rather, aging is subject to various influences and is a process that is regulated genetically, by the environment and by behavior.
Aging is an important risk factor for many diseases.
Everyone knows from personal experience that aging is associated with an increased likelihood of many diseases. Dementia, cardiovascular diseases, cancer and diabetes are particularly important here. Many old people suffer from several of these diseases at the same time. This multimorbidity is the reason why human life expectancy would only increase by an average of around two to three years if cancer were curable. It is therefore particularly important to understand biological aging as such, because if aging is slowed down, the likelihood of all age-associated diseases decreases.
The biology of aging can be studied in simple animals
Since aging is a fundamental biological process, underlying mechanisms can be investigated in less complex organisms. A class of genes was discovered in yeast cells that also play an important role during the aging of mammals . In the simple nematode Caenorhabditis elegans many genes have been identified that affect aging. It could be shown that individual mutations within the insulin receptor can multiply the life span (Fig. 1; ).
In worms, as in humans, insulin is a hormone that signals the availability of food, i.e. energy, to the cells. This indicates an important principle in geriatric biology: If the availability or perception of energy from food is disturbed, protective processes are triggered that slow down aging. This is also confirmed in the calorie restriction, namely the intervention that apparently universally increases life expectancy: Reduction in food intake has so far led to increased life expectancy in all the organisms examined. Of course, this cannot be systematically investigated in humans, but calorie restriction seems to lead to improved health in us too .
Genetic screens can identify new longevity genes
To study the regulation of aging, genetic screens can be used in C. elegans be performed. First, random mutations are brought about in the worms' DNA. The majority of these mutations have no effect or have a rather negative effect. There in C. elegans but hundreds of thousands of individual genomes can be examined simultaneously, identifying the rare mutations that increase life expectancy. It has been shown that activating mutations in an enzyme involved in sugar metabolism can increase life expectancy . The hexosamine synthesis route, for example, uses glycolysis intermediates to produce more complex sugar molecules that are not metabolized, but used in synthesis processes. The product of the hexosamine synthesis route is UDP-N-acetylglucosamine, and its synthesis can be increased by activating mutations in the key enzyme or by adding N-acetylglucosamine. This results in C. elegans not only to increased life expectancy, but also to special protection against toxic proteins. These toxic proteins play an important role in dementia in particular, as certain endogenous proteins become insoluble over time and toxic aggregates accumulate. The amyloid plaques in the brains of Alzheimer's patients or the glutamine peptides in the brains of Huntington's patients are examples of this. Heterologously expressed human toxic proteins can be investigated in transgenic worms, since these lead to paralysis in worms as in humans. Activation of the hexosamine synthesis pathway protects against the effects of various toxic proteins associated with dementia.
The hexosamine synthesis route is an essential process. All cells need UDP-GlcNAc for the synthesis and modification of proteins, for example. This also applies to the cells of higher organisms and in this context one speaks of conservation when a biological process is maintained in the course of evolution between distantly related species. The hexosamine synthetic route is actually highly conserved and its enzymes are almost identical when comparing worms and humans. Does UDP-GlcNAc also protect against toxic proteins in human cells and could this be important in connection with dementia? Toxic proteins could be investigated in cell culture and the administration of GlcNAc actually reduced the accumulation of toxic glutamine peptides in cultured neuronal cells.
These observations suggest that knowledge from genetic screens is using C. elegans could be transferable to human biology. Genetic screens allow systematic questioning of the entire genome for age-relevant genes. This led to the finding of surprising candidates, as presented here for the identification of activating mutations. It seems particularly important here that the function of individual genes does not have to be examined with the help of KO mutations that completely switch off a gene. Rather, at the level of the individual building blocks of proteins, the amino acids, it is possible to investigate which changes lead to longevity; these can then be validated in cells from higher animals or in mice.
For ethical as well as practical reasons, it will not be possible to increase human life expectancy by deliberately mutating certain genes. The investigation of longevity genes in model organisms can rather identify those molecular and genetic processes that are relevant in the biological regulation of aging. With this knowledge, drugs against age-related diseases could then be developed.
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