Daniel Promislow, PhD, on Genetics and Aging

While you may have the genes for red hair and blue eyes, contrary to common thinking, one gene alone or even two won’t determine whether you will develop a disease or live a long, healthy life – even with a strong family history. In a new area of aging research called systems biology, scientists are looking at the interacting mechanisms of hundreds of genes and gene networks to better understand the larger context of the causes and consequences of aging. This may one day tell us why faster rates of aging and onset of inheritable diseases occurs in one sibling and not another. Dr. Daniel Promislow, a recipient of the Glenn/AFAR Breakthroughs in Gerontology (BIG) Award, answers some questions about this fascinating area of aging research.

What is systems biology and what is its place in aging research?

Aging is an incredibly complex phenotype and the underlying causes of it are very complex. It is highly unlikely that there is a single gene that explains all the variation we see in the rates of aging within a species whether it is in yeast, fruit flies, or humans. There are many molecules, cells, genes, and metabolites all interacting with each other. Systems biology is the study of the complex network of interactions that move an organism along the path from its genotype and environment to the final phenotype, whether that’s eye color or body height or life expectancy.

As an evolutionary biologist, I am interested in the variation between species and within species as a way to understand why some families are full of long-lived people and other families are full of short-lived people. Systems biology helps us embrace the complexity of aging.

What do you mean by evolutionary biology?

We have all heard of natural selection – survival of the fittest. Well, in the early 20^th century, theories of aging – from Peter Medawar in 1946 to George Williams in 1957 – proposed that while natural selection would get rid of deleterious mutations that reduce survival or reproductive capacity early in life – what is called evolutionary fitness – those that acted late in life would be much less visible to selection and therefore quietly spread from generation to generation.

Now that we are living longer, we are seeing the effects of these late-acting mutations. This is why we are seeing more cases of Alzheimer’s disease, for example. The genetic variation for Alzheimer’s disease was likely there all along but was only expressed once we started living longer. One hundred years ago, lifespans were shorter so there wasn’t enough time for the effects of those genes to emerge.

In his classic 1957 paper, George Williams argued that the genes with deleterious effects late in life might have spread through a population because they once had early-age beneficial effects and thus natural selection did not recognize them as undesirable.

The study of systems biology combines the evolutionary theory of aging – the “whys” – with the mechanistic theories of aging – the “hows.”

If a mother and grandmother had Alzheimer’s disease, is it genetically pre-determined that the daughter will get Alzheimer’s as well?

No. Just because someone has a genetic link to a disease – even a strong one – doesn’t mean it is inevitable that they will inherit a disease. There is not simply one gene for one behavior or expression; there may be thousands of other elements involved, including environmental factors that trigger a disease to occur or rates of aging to slow or accelerate. We can identify a gene associated with a trait – in this case Alzheimer’s disease – but we don’t know how this one gene interacts with thousands of other genotypes. And that’s what systems biologists are looking at.

Isn’t that painstakingly complex?

Actually, it isn’t because rather than looking at one gene at a time, we are looking at a whole system.

For example, in the fruit fly, we are interested not just in how individual genes change expression pattern with age, but rather in how the structure of the overall network changes with age. In a study of the gene expression network in mice, Stanford researchers Lucy Southworth and Stuart Kim showed that the number of connections in the network declines with age. Here, ‘connections’ are defined by pairs of genes that appear to increase or decrease their level of expression in tandem across different tissue types. In my own work, I’m interested in finding out more about this apparent loss of network integrity with age, using both genetic and metabolomic networks. My hope is that eventually, we can study age-related changes in network structure and function just as now we might study age-related changes in muscle strength or cognitive function.

What other research are you and your colleagues doing?

In my lab, we are studying the effects of reproduction on lifespan. In fruit flies, if you limit the amount that they can reproduce, they live longer. Researchers have discovered genes in fruit flies that, when knocked out, extend lifespan. But these genes also decrease fertility. We are interested in identifying genes that affect natural variation for lifespan, and asking whether these genes also affect traits related to reproduction. In general, we are interested in using the fruit fly as a way to determine whether what we learn in lab-adapted organisms, knocking out one gene at a time, applies to the world of highly genetically variable populations living in complex environments (like us!).

We have also been studying health and lifespan in dogs, which is really a perfect model to explore the genetics of disease. They are very diverse in terms of the number of breeds but they all evolved from the same species (the wolf), so that gets back to our interest in studying aging within and between species. In mammals, larger species tend to live longer than smaller ones, but within a species we sometimes see the opposite effect. Small dogs live much longer than big dogs. We don’t know why yet but this is something we are working on. And given that dogs share their environment with humans, we are hopeful that some of what we learn about the factors that affect canine lifespan might help us to better understand human lifespan.

In research funded by AFAR, we are looking at networks of small molecules (metabolites) in fruit flies with the goal of identifying the network components that change with age, and ultimately, the factors that affect rates of change in network structure.

And finally, when you meet people, what kinds of questions are you asked?

People are always interested in knowing whether they will live a long life if their grandparents did. And while it would certainly help to choose long-lived parents if you could, I’m afraid my answer is not an original one: we can dramatically increase lifespan and reduce the incidence of developing diabetes, cancer, and heart disease by eating a healthy diet and exercising.

06/21/12