| The relationship between age and health varies from person to person. Take successive U.S. presidents for example. Ronald Reagan developed Alzheimer’s disease in his 80s and died from complications of the disease at 93; Franklin Roosevelt died of a brain hemorrhage at 63. ; Jimmy Carter, the oldest living president in American history, suffered from cancer at 95 and is still alive at 98. Beyond age, the environment also affects health. Even identical twins with identical genomes have differences in gene expression with age, implying that the environment modulates gene expression.
In fact, with age, gene expression levels change and many biological processes deteriorate, leading to cell dysfunction and worse tissue activity. Medawar’s theory of germline mutation accumulation states that because older individuals are less likely to contribute their genetic information to the next generation, late-onset mutations accumulate much faster than early-onset mutations. In this case, natural selection is weaker and cannot consistently eliminate these mutations. Over time, these harmful late-onset mutations will accumulate and lead to aging. However, how to quantify the tissue-specific effects of increasing age and genetics on gene expression patterns is inconclusive.
On October 3, 2022, a research team from the University of California, Berkeley, published a study titled "Tissue-specific impacts of aging and genetics on gene expression patterns in humans" in Nature Communications. Research shows that age plays a more important role than genetics in determining which genes are expressed in our bodies and affects susceptibility to disease.
The study established a statistical model to assess the relative roles of genetics and aging in 27 different human tissues from 948 individuals and systematically assessed the relative effects of genetics, aging and environment on the expression patterns of approximately 20,000 human genes.
The results turn out:
01 Gene expression prediction: little effect in old age
The human genetic makeup can help predict gene expression at a young age, but it is less useful in predicting which genes will increase or decrease in old age. Age affects the predictive power of expression Quantitative Trait Loci (eQTL), but to varying degrees in different tissues and in older and younger individuals: younger individuals are significantly better than older individuals for genotype expression prediction.
02 Gene expression is influenced by the environment: increases with age
Traits are determined by a combination of genetic and environmental factors. The concept of "heritability" refers to the proportion of a trait that is genetically regulated. The higher the heritability, the greater the proportion of genetic factors and the smaller the proportion of environmental factors in the determination of traits. Gene expression heterogeneity differs between young and old in many tissues. The increased expression differences reduced the average heritability of gene expression in these tissues, both in the elderly and in the young.
03 Age-influenced tissue aging: cancer-prone tissue limits life
The average heritability of gene expression was largely consistent across tissues. While the expression of many individual genes is strongly influenced by genetics, genetics explains a small fraction of overall gene expression. In contrast, age contributed on average 20-fold more than genetics to changes in gene expression in tissues. The coordinated decline of mitochondrial genes and translation factors is a ubiquitous phenomenon of aging across multiple tissues, with potential phenotypic consequences.
Age-related gene expression patterns exhibited more tissue specificity than genetically influenced gene expression patterns, and in five tissues (blood, colon, arteries, esophagus, fat) age was a driver of gene expression patterns is much stronger than genetics. These five tissues happen to be the ones that change throughout a human life and are the ones that generate the most cancers. Every time these tissues renew themselves, there is a chance of developing genetic mutations that cause disease. In the later years of human beings, these genes are easily affected by somatic mutations and exist in a cancerous manner, limiting the normal operation of the body and limiting the development of life.
This study found that aging and the environment are far more important than genetic variation in influencing gene expression in humans; genes with eQTL tend to be less evolutionarily constrained than genes with age-related gene expression patterns, so potential biological Learning is less important. The insights provided by this study on tissue-specific aging patterns and the relative effects of genetics and aging on gene expression will facilitate future studies of gene expression, chromatin structure and epigenetics across tissues and cells. Elucidating how programmed and stochastic processes of aging drive human disease.
"Scientists have done a lot of work in human genetics to understand how human genetic variation regulates genes," said corresponding author Peter H. Sudmant. "Our project addresses this question: How does age affect gene expression? We found that with age Genetics is actually less and less important. These findings have important implications for research linking diseases of aging to genetic variation in humans: such research should perhaps pay less attention to genetic variation that affects gene expression in the pursuit of drug targets .Almost all common human diseases are diseases of aging, such as Alzheimer’s disease, cancer, heart disease, diabetes, etc., and the prevalence of these diseases increases with age. Numerous public resources have been used to identify easy Genetic variants that develop these diseases. In fact, as we age, genetics has less and less influence on gene expression. Maybe, when we try to determine the cause of these diseases of aging, we need to be aware of that.”
Regarding the main factors that affect gene expression, Sudmant said: "The environment accounts for one-third of the change in gene expression with age. The air we breathe, the water we drink, the food we eat, and our level of physical activity are all environmental factors. We all age in different ways, but the expression of genes in older people is increasingly unstable. Genetics are about the same in all tissues of your body, but aging varies greatly between tissues, age Plays a much stronger role than genetics in driving gene expression patterns. From an evolutionary point of view, some super-conserved, very important genes must be activated later in life. Actually, this is problematic because it means These genes are susceptible to somatic mutations and are permanently activated in a cancerous fashion. So, it limits our ability to continue living and suggests the limits of our evolution."
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