Why we age
Is longevity written in our genes or do we all have the capacity to live into old age?
In my previous article, I outlined why the science indicates that preventing (or at least slowing) aging is one of most strategic steps we can take to combat rising rates of chronic disease globally.
But if we want to do something about aging, then we need to understand what causes it. Below I’m going to outline what the science tells us about why we age and what causes aging. If you want to find out whether it’s all predetermined in our genes or whether we can take our destiny in our own hands, keep reading.
Why we age — it’s all about evolution
If humans and their close ancestors have been evolving for millions of years, then why haven’t we been optimized over all these years to live more efficiently and live longer without disease or becoming frail?
To answer that question, let’s think for a moment about how evolution and natural selection work. Natural selection is like a big population filter. Those who are better adapted to their environment will have a greater chance to survive than those who are not well adapted. This leads to a very long process of genetic refinement where the genes and traits that give us some advantage in the world are passed on to our children because they allow people to live long enough to reproduce. The genes and traits that don’t give us an advantage (or worse, a disadvantage) tend not to be passed on because those who have them might not live long enough to reproduce.
This means that natural selection really only applies pressure on human traits until the age of reproduction. If certain genes or traits that prove beneficial for survival until reproduction but have harmful effects on our health after reproductive age, Natural selection will allow us to keep and pass on these traits because it cannot “see” the harmful effects later in life. Natural selection only cares about what allows you to live until you reproduce. People with these traits that might be harmful later in life will pass them on to their children just as easily as others. An interesting example is the APOE4 gene, which is known to influence Alzheimer’s and cardiovascular disease, but may actually provide a benefit for fertility earlier in life.
As the years go by, we all accumulate lots of damage and degradation in our bodies. From the sun’s UV rays, to stress and hunger, to daily wear and tear, our bodies are under constant assault. Of course, humans have lots of built in biological repair mechanisms to identify this damage, repair it, and maintain ourselves in a healthy state. Throughout human evolution, however, natural selection has only required that these repair mechanisms be efficient enough to keep us healthy until reproductive age. Evolutionarily speaking, we have not developed as a species to repair and deal with the accumulation of damage and degradation that we face in the decades that follow reproduction. There are no evolutionary forces that require our body’s ability to repair itself to continue functioning efficiently after we have children. In practical terms, this means that as we grow older, we are more and more susceptible to becoming frail and succumbing to disease.
How our genes contribute to lifespan
Whether there is a genetic limit to lifespan is still contested. But the fact remains that human lifespan has almost doubled over the past 200 years. This time span is far too short for genetics to have caused this jump in life expectancy. However, this doesn’t mean that genes don’t play a role. In human population studies where researchers scan the entire genome to find genes most strongly involved in a specific outcome (so-called genome-wide association studies, or GWAS), a limited number of genes have been found to be associated consistently with long lifespan. These include apolipoprotein E (APOE), forkhead box O3 (FOXO3A), and cyclin dependent kinase inhibitor 2A and 2B (CDKN2A/B).
Of the longevity genes discovered to date, only APOE has been among the strongest associations across multiple GWAS publications. The APOE gene is involved in a large number of age-related diseases, including Alzheimer’s disease and ischemic heart disease. However, we still don’t fully know the mechanisms through which APOE is involved in longevity.
Studies have also consistently shown the FOXO3 gene to be associated with aging and longevity across mammal species. FOXO proteins are involved in many biological processes related to aging, including regulating stress resistance, metabolism, and apoptosis (programmed cell death). The FOXO3 gene has been associated with a large number of aging-related traits including insulin-like growth factor 1 (IGF-1) levels, kidney function, cognitive function, and lung function. However, it’s worth noting that the FOXO3 gene has not yet been found to be significantly associated with age-related diseases themselves in any GWAS conducted to date.
And lastly, CDKN2A and CDKN2B have been consistently associated with longevity across studies. Of interest is that these genes, and the regions between the genes, are involved in cellular senescence (stopping of cell division and growth) and have also been associated with age-related diseases such as coronary artery disease, stroke, diabetes, glaucoma, and melanoma.
But what about really long life? Do genetics play more of a role there? Interestingly, a recent study of semi-supercentenarians and supercentenarians (105+/110+ years of age) found that those who live to between 105–109 years of age share a common genetic background that is associated with efficient DNA repair mechanisms. This makes a lot of sense given our discussion above on the importance of bodily repair with age. It might be that those who get lucky genetically are more able to deal with all the repair our bodies need to do across really long time frames (100+ years).
It’s interesting to note that several recent genetic studies in long-lived families also identified parts of the IGF-1 receptor (IGF1R) gene that may be important for long life. These findings bridge the gap between genetic research on human longevity and the overwhelming evidence in experimental research in animals linking IGF-1 to lifespan.
Ultimately, despite the discovery of certain genes associated with longevity, the heritability (how well we can predict a trait from genetics) of lifespan has been shown to be low. Different studies estimate the genetic heritability of lifespan to be between 12–25%. One very cool study published in Science collected 86 million publicly available profiles from a crowd-sourced genealogy website to study how genetics relatives to longevity and lifespan. They found, however, that the heritability of longevity was only 12.2%, meaning that (at least in their study population) 87.8% of longevity must be explained by something other than genetics.
The environment, health care, and population health
So if it’s not our genes that determine how long we live, then what does? In this case, all signs point towards our environments. Here I’m going to use the word “environment” in the broadest possible sense to refer to physical (e.g., pollution, greenspace, neighborhood quality) and socioeconomic (income, deprivation) environments, as well as individual behaviors (e.g., smoking), lifestyles (e.g., physical activity), and treatment landscapes (e.g., access to quality health care and medicines).
Global health care and public health have changed dramatically over the past two centuries, as have the physical and social environments in which we live. The huge increase in human lifespan during the past 200 years has largely been attributed to changes in human environments — improved water and food quality, hygiene, reductions in malnutrition, better housing and lifestyle, motor-vehicle safety, safer workplaces, immunization against infectious disease, antibiotics, and improved medical care. Throughout European history over the past several centuries, improvements in population health and longevity have been closely related to improvements in medical care and public health, as well as economic, social, and political environments.
Throughout human history, diseases arise as a reaction of human biology to our environments. While there certainly exist diseases that are caused primarily by genetic defects (e.g., Huntington’s disease and Down’s syndrome), these are relatively rare and are not related to age or rates of aging. Johan Mackenbach has conducted extensive historical work documenting the rise and fall of diseases over the past several centuries in Europe. He shows that many of the major disease epidemics during this period (both in terms of infectious and non-communicable disease) have occurred in a small enough time-scale to rule out spontaneous (i.e., genetically driven) changes as the root cause. Instead, Mackenbach shows that the majority of diseases (both infectious and non-communicable) must arise from the interaction between humans and their environments.
Over the past century, public health interventions (e.g., improved water and food quality, hygiene, motor-vehicle safety, safer workplaces) have played a large and decisive role in the decline of many deadly diseases, including plague, smallpox, typhus, cholera, lung cancer, and liver disease. Advancements in medical care and medicines, especially antibiotics, have also played a large role in reducing deaths from infectious disease, stroke, and cardiovascular disease. Governments and politics also have a role to play. Governments that take measures to protect health, run complex health care systems, and distribute wealth to benefit health, have been crucial to increasing life expectancy over the past century.
Outside of improvements to public health and medical treatment, many behavioral, lifestyle, and socioeconomic factors have been identified that play a role in lifespan and mortality. In 2013, the World Health Organization (WHO) published a landmark report with a global action plan to reduce premature mortality from non-communicable diseases by 25% by 2025. Drawing from decades of epidemiological evidence, the report identified seven major risk factors that are leading contributors to global chronic disease burden and premature mortality, including alcohol, insufficient physical activity, tobacco use, high blood pressure, intake of salt or sodium, diabetes, and obesity. These are often referred to as the WHO 25 x 25 risk factors. The most recent and largest global analysis of premature mortality to date (conducted using 1.7 million study participants) shows that the number of years of life lost due to smoking, high vs. low socioeconomic status (SES), and physical inactivity are on average 4.8, 3.4, and 2.4 years, respectively (23).
Social support is another environmental influence that is consistently associated with mortality across numerous studies, showing that those without social support are 11–53% more likely to die early than those with support. Air pollution has also been shown to dramatically shorten life expectancy in the US population above 65 years old.
Environmental factors have not only been linked with mortality, but also with the age at which we develop age-related diseases. For example, in a recent analysis of 1.8 million people in Scotland, those living in areas that were deprived socioeconomically developed multiple chronic diseases simultaneously (multimorbidity) 10–15 years earlier than those in the wealthiest areas.
Mixing nature and nurture
Ultimately, aging is a complex story. The combinations of influences are simply too great for us to tell the full story with either genetics or environmental information alone. In the messiness of real life, what often happens is that environmental influences interact with our underlying genetic composition to shape our risk of developing disease and dying. To begin with, those with a particular genetic makeup may be more sensitive to environmental influence that others. For example, those who have certain versions of the APOE gene may be more sensitive to the impact of stress, social support, and depressive symptoms on cognitive function (memory, reasoning, planning, problem solving, multitasking).
Another interesting example of gene-environment interactions comes from research on caloric restriction (reducing your daily caloric intake). Caloric restriction, as a form of environmental manipulation related to diet, has been shown to increase lifespan in a number of animal studies. Interestingly, mutations in several genes associated with lifespan and longevity, including IGF1R and FOXO3, have been shown to modify or cancel out the life extending effect of caloric restriction.
Overall, while changes to our genetics have likely not contributed to changes in human life expectancy over the past 200 years, genetic differences among individuals throughout human history have certainly been interacting with changing human environments to jointly shape who dies young and who lives long into old age. It’s true that some of us may be slightly luckier than others in terms of genetics. But the good news is that we all have the capacity to live well into old age, so long as we are in a position to find an environment that allows us to thrive and live well.
Austin Argentieri is researcher at Harvard and the Broad Institute. His work is focused on using big data, machine learning, and biological data to better understand human aging and predict age-related diseases. Austin can be found online at austinargentieri.com. For more regular updates on ideas, stories, and developments in aging research, you can follow him on Twitter and LinkedIn.
