Longevity and Genetic Trade Offs

Genetic variants, or polymorphisms, are the common changes that can affect gene function a little bit. These changes make us all unique – from traits like hair color or eye color to the things that ‘run in the family’, like diabetes or heart disease.

It has been theorized that our human lifespan is a compromise between longevity and early life growth and reproduction. The idea is that genes and biological pathways important earlier in life can be a driver of diseases of aging. For example, you want cellular growth in youth, but out-of-control cellular growth is a hallmark of cancer. So a balance is needed.

A new 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 utilize tens to hundreds of genetic variants known to influence a specific chronic disease. For example, diabetes risk is driven by many different genes.

This method of using polygenic risk scores is different than just looking at single genes or genome-wide association studies for longevity. It shows which pathways are likely to be most important in aging – where we can all focus.

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. Check out Genetic Lifehacks to figure out what your genes can show you as far as genetic susceptibility.

Getting to the point:

The study showed that there were 134 complex phenotypes that seem to impact longevity.

Negatively impacting longevity included increased genetic risk of:

  • 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, fracturing a hip rarely has a good prognosis.

Positively associated with longevity include:

  • schizophrenia
  • autism spectrum disorder
  • cannabis disorder
  • insulin-related traits and type 2 diabetes
  • atopic dermatitis

Surprising (to me) was that schizophrenia polymorphisms and type 2 diabetes polymorphisms were associated with longevity. People who have diabetes or schizophrenia are likely to die at earlier ages, but for people with certain genetic risk factors who don’t develop the diseases, those polymorphisms seem to hold a longevity advantage.

For schizophrenia, the researchers further investigated these associations and found that there were both positive and negative longevity effects from different schizophrenia-related polymorphisms. The polymorphisms with a positive link to longevity were linked to hyperactive immune response. A hyperactive immune response in the brain is one factor involved in developing schizophrenia. In people who don’t have schizophrenia, the overactive immune response may be of benefit 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 those same variants may help maintain blood glucose levels in the brain during aging.

The study authors conclude with a reminder that the environment (diet, pollution, virus exposure, drugs, light exposure, etc.) interacts with the polymorphisms. The genetic variants linked to diabetes may be beneficial when the diet is low in carbohydrates. Additionally, what is a positive at one stage in life may be more of a negative at another stage in life.

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