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Zeroing in on the Genetics of Human Aging

Scientists review research linking variations in people’s DNA to aging.

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By Bennett M. Sherman

Aging occurs all over the tree of life, yet it remains difficult to define. Researchers describe aging as the reduction of functional abilities with time that typically begins after sexual maturity. Functional changes that occur at the cellular level, known as biological “hallmarks” of aging, result in diminished functional capabilities in the performance of everyday physical and cognitive tasks, such as taking out the trash or remembering where you left your car keys. To what extent variations in the inherited sequences of DNA contribute to the emergence of these “hallmarks” has not been fully understood.

Recently, Melzer and colleagues from the University of Connecticut and the National Institute on Aging published a review in Nature Reviews Genetics looking at how scientists have used genetics research to uncover what goes on inside of cells during human aging. They described how scientific investigators want to use this research to figure out how to sustain longer lives and reduce periods of disability with the unprecedented increase in human life expectancy over the last two centuries.

In their review, Melzer and colleagues present findings from genome-wide association studies (GWAS), an approach used in genetics research to link variations in DNA from many people to particular diseases. In examining the DNA variations that associate with longevity, these studies zeroed in on a particular gene that plays a role in longevity called APOE. Interestingly, this gene codes for a protein involved in transporting cholesterol to cells and functions in the brain to maintain and repair connections between neurons, which are called synapses. Thus, there is likely a link between certain inherited DNA sequences in this gene and the onset or impact of Alzheimer’s and cardiovascular disease.

Melzer and colleagues also presented analyses on DNA variants that play significant roles in influencing longevity and aging as well as multiple age-related diseases like Alzheimer’s or coronary artery disease. They uncovered 22 genetic variants that are linked with multiple age-related diseases, 12 of which were linked and mostly inherited together. One of these 12 genetic variants was found in APOE and was linked with Alzheimer’s and coronary artery disease. Two other DNA variants were located in the genes LPA and LDLR and were linked to altered blood fat levels (blood lipids) and cardiovascular traits. The remaining nine associations between genetic variants that tend to get inherited together and age-associated diseases included links to three or more of the diseases, including Alzheimer’s disease, stroke, coronary artery disease, type 2 diabetes, kidney disease, osteoarthritis, and several cancers.


(Melzer et al., 2020 | Nature Reviews. Genetics) Genetic variants that tend to get inherited together in nine genes were linked with multiple age-related diseases. The associations of DNA variants in these genes with specific diseases are illustrated in the diagram as colored lines. AD, Alzheimer’s disease; CAD, coronary artery disease; CKD, chronic kidney disease; OA, osteoarthritis; T2DM, type 2 diabetes mellitus.

Determining how human aging occurs at the level of DNA and cells remains in its early phases. The ability to balance DNA damage with repair processes seem to be emerging as a driving force behind aging processes. Data from GWAS studies indicate that genetic variants linked with age-related diseases can play influential roles in these processes.


(Melzer et al., 2020 | Nature Reviews. Genetics) Mechanisms of human aging. Evidence from genetic studies of aging supports the proposal that aging processes come from a balance of damage and repair mechanisms. The impact of DNA damage grows with chronological age as DNA repair becomes reduced, causing cells to die (apoptosis), stop replicating (senescence), or accumulate cancer-causing mutations. Ultimately, this results in an increase in the onset of chronic diseases of aging or cancer.

“Human genetics will likely continue to provide growing insights into how we age and play a major role in identifying ways in which we might slow ageing, thus helping more people to age well,” stated Melzer and colleagues in their review. Researchers have begun to define the genes leading to aging which could lead to therapeutic options soon. Understanding the roles genetics plays can lead to treatments to sustain longer lives with reduced periods of disability and disease.

Source

Melzer D, Pilling LC, Ferrucci L. The genetics of human ageing. Nat Rev Genet. 2020 Feb;21(2):88-101. doi: 10.1038/s41576-019-0183-6. Epub 2019 Nov 5. PMID: 31690828.

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