Longevity and Genetic Trade Offs
Genetic variants are slight changes in a gene that can affect the function of genes. These little variations make us all unique - from traits like hair or eye color to things that "run in the family" like diabetes or heart disease.
It has been theorized that lifespan is a trade-off between longevity and early life growth and reproduction. The idea is that genes and biological pathways that are important early in life may end up being a driver of diseases of aging. For example, you want cell growth in youth, but out-of-control cell growth is a hallmark of cancer. So a balance is needed.
Looking at polygenic risk to determine what is important in aging.
A 2022 study looked at the genetic variants that influence traits and disease risk, comparing centenarians to an average middle-aged cohort.
The researchers used polygenic risk scores for 225 complex traits and diseases. Polygenic risk scores use tens to hundreds of genetic variants known to influence a particular chronic disease. For example, the risk of diabetes is influenced by many different genes. A polygenic risk score for diabetes incorporates both the protective variants and the risk variants to give a bigger picture of your risk of diabetes.
Polygenic Risk Scores give longevity researchers a different picture than just looking at single genes or genome-wide association studies. It shows which pathways are likely to be most important in aging.
The study showed that there were 134 complex phenotypes that seemed to impact longevity.
Those that negatively affected longevity included an increased genetic risk for:
Parkinson's disease
inflammatory bowel disease
stroke
coronary artery disease
kidney disease
very-low-density lipoproteins (VLDL)
fracture risk
height
waist circumference adjusted by BMI
These all make sense -- you're less likely to live to 100 if you have a stroke or heart attack. Similarly, breaking a hip rarely has a good prognosis. Being tall has long been known to reduce average life expectancy somewhat.
What I found more interesting were the genetic pathways linked to longevity.
Positively associated with longevity include:
schizophrenia
autism spectrum disorder
cannabis disorder
insulin-related traits and type 2 diabetes
atopic dermatitis
Most surprising to me was that schizophrenia and type 2 diabetes polymorphisms were associated with longevity. People who have diabetes or schizophrenia are likely to die at an earlier age, but for people with those genetic risk factors who don't develop the diseases, these polymorphisms seem to confer a longevity advantage.
For schizophrenia, the researchers further investigated these associations and found that there were both positive and negative longevity effects of different schizophrenia-related polymorphisms. The polymorphisms with a positive association with longevity were associated with a hyperactive immune response. A hyperactive immune response in the brain is one factor involved in the development of schizophrenia. In people who don't have schizophrenia, the overactive immune response may be beneficial later in life in fighting off infectious diseases.
In people with genetic polymorphisms that increase the relative risk of type 2 diabetes, the researchers hypothesize that the same variants may help maintain blood glucose levels in the brain as people age.
The study authors conclude by noting that the environment (diet, pollution, virus exposure, drugs, light exposure, etc.) interacts with the polymorphisms. For example, the genetic variants associated with diabetes may be beneficial when the diet is low in carbohydrates. In addition, what is positive at one stage of life may be more negative at another stage of life.
Narrowing the focus for an individual:
Understanding your own individual risk of a chronic disease can also help you to understand where to focus your efforts for healthspan and healthy aging.
On the positive side, if you do have type 2 diabetes-related variants but watch your diet and don’t develop diabetes, those variants seem to be beneficial.
Understanding your genetic risk for negative longevity traits, like coronary artery disease or Parkinson’s disease, can help you understand where to prioritize your health efforts. For example, people with BChE and PON1 variants are at a significantly increased risk of Parkinson’s with organophosphate exposure.
Check out Genetic Lifehacks to see what your genes show for genetic susceptibility.
My final two cents:
The polygenic risk scores for diseases are being used to select the 'best embryo' for in vitro fertilization. This study is a reminder that there is a lot we don't yet know. Parents who are selecting embryos to avoid a risk of schizophrenia may be unknowingly selecting for a shorter lifespan.
Reference: Hu, D., Li, Y., Zhang, D., Ding, J., Song, Z., Min, J., Zeng, Y., & Nie, C. (2022). Genetic trade‐offs between complex diseases and longevity. Aging Cell, 21(7). https://doi.org/10.1111/acel.13654
