How genes, sex, growth and age impact lifespan

Aging, senescence, and death are given as inevitable. Some people age faster, some suffer from age-related diseases, and some die younger than others. Robert Williams at UTHSC who jump-started this project with Johan Auwerx at the EPFL in 2016 points out that "Finding common molecular denominators of aging differences is critical. Lifespan and health are under some level of genetic control that varies both within and between species. Once defined we can then intervene rationally."

The problem is that lifespan—the duration of time one lives—is one of the most complicated traits that one can study and is affected by genes and the environment as well as their complex interactions. This complexity renders the study of aging and lifespan challenging in humans, each of whom have their unique genetics and environmental exposure histories. Studies in laboratory organisms under controlled environments attempt to decipher these now more simplified relations to provide insights into this complex process.

Researchers within a consortium led by EPFL and UTHSC have moved one step closer to understanding these relationships by studying lifespan in the largest mouse longevity study to date, the National Institute of Aging’s (NIA) Interventions Testing Program (ITP). The ITP, launched in 2004, is a multi-institutional program designed to test the effect of different treatments on longevity. To simulate a human population, hundreds of genetically different mice of both sexes, were treated in three different locations: The Jackson Laboratory (led by Prof. David Harrison), the University of Michigan at Ann Arbor (led by Prof. Richard Miller), and the University of Texas Health Science Center, San Antonio (led by Profs. James Nelson and Randy Strong). This combination of different sites and truly diverse mice allows researchers to find life-extending treatments that are generalizable across individuals, environments, and even species.

Genetic determinants of longevity are specific to one sex or only make a difference past a certain age.

Since untreated (or control) mice are included as a reference for each intervention, a large number of such mice now have become a treasure trove of data to study the determinants of natural lifespan. EPFL and UTHSC researchers measured the genetic makeup of more than 3000 individuals from one enormous mouse family from small piece of tail clipped when the mice we only 30 days old. Once genotyped and aged out to natural death, they explored the relationship between DNA difference and differences in the lifespan of each mouse. This genetic mapping allowed the teams to define stretches of DNA in the genome that affect longevity. “We found that the DNA segments, or loci, that are associated to longevity are largely specific to each sex. Females have a region in chromosome 3, that affects lifespan, but this region has no effect in males. Many males die younger due to non-aging-related reasons such as fighting and cancers. This is why when we removed males who die early from the analysis, genetic signals started to emerge. What is intriguing is that depending on the age threshold, new loci arise, which suggests that some genetic variations only become relevant (affect lifespan) after attaining a certain age” comments Maroun Bou Sleiman from the LISP at EPFL.

Genetics and early growth affect longevity

In addition to finding genetic determinants of longevity, the researchers explored other contributors. The relationship between how fast and how much an organism grows with longevity has already been described. In general, bigger mice die younger. They show that some, but not all, of the genetic effects on longevity are through effects on growth. So what are those non-genetic effects? One of them is how early access to food affects growth. Maroun Bou Sleiman discusses “We observed that mice that come from smaller litters (having fewer siblings) tend to be heavier at adult ages, and live shorter. Mice from larger litters have to share their mother’s milk with more siblings, and would therefore grow slower and live longer on average”. The researchers corroborate these trends and additionally show an opposite impact of early vs late growth on longevity in large human datasets with hundreds of thousands of participants in a collaboration with the team of Zoltan Kutalik at the Université de Lausanne.

The hunt for aging and longevity genes

Beyond characterizing how longevity is affected, the researchers focused their attention on finding the most likely genes that play a role in longevity determination. They measured the effect of DNA variation on how genes are expressed and compared their analyses with multiple human and non-human databases. This allowed them to nominate a few genes that are likely candidates to modulate aging rates. They then tested the effects of manipulating these genes in round worms (C. elegans) and found that a subset of gene perturbations did in fact affect the lifespan.

The future lies in healthspan research

This study is an important step in understanding the factors behind why some people live longer than others. However, Johan Auwerx, one of the lead authors of the study comments “This particular study is focused on longevity, yet what is arguably more important is how long health is maintained. This is referred to as ’healthspan‘, the period of life that is disease-free. Studies in animal models and ultimately in humans will need to assess how the health degrades in a longitudinal manner, and then search for the underlying causes. We are in the midst of such a healthspan study in our laboratory”. A main question remains: can one postpone many diseases at once by affecting aging globally? The results of this study will be a rich resource of aging genes that will hopefully guide the design of therapies that not only extend lifespan, but also healthspan.