Reddit “Ask Me Anything (AMA)”: RNA splicing and aging

Will Mair, assistant professor of genetics and complex diseases, participated in a reddit “Ask Me Anything (AMA)” on January 9, 2017, to discuss a recent study that uncovered a “smoking gun” in age-related disease. The paper, published in Nature, reveals a causal link between a process known as “RNA splicing” and aging. Mair and his co-authors shed light on when and how our cells deteriorate over time. Aging is a key risk factor for a variety of chronic diseases, and Mair’s lab is working to identify what’s happening at the molecular level in various organ systems that allows these diseases to occur.

Here are some highlights from the AMA, and you’ll find a link to the full conversation below.

What are some potential applications of this research?

The goal of our work is certainly not to make nematode worms live longer—but to use them as a lab tool to expedite the discovery of new processes that link age to disease risk. Our work shows that deregulation of the RNA splicing process can predict animals that age faster, and that interventions such as mTORC1 suppression or activation of splicing factor 1 can slow aging and maintain animals in a youthful state for longer. The long term goal of our work now is to try and translate these findings to mammals to develop novel therapeutics for age-related diseases. We have already shown that some of the effects of splicing factor 1 in nematodes are also seen in human cells, and we are actively developing this line of research. This will take some time and effort, but the long term application to patients is therefore that we might use specific RNA splicing changes both as biomarkers of health and also as predictors of the response to a treatment. Lastly, if the effects of activating splicing factor 1 on health in C. elegans are conserved to mammals, this might open up new avenues for therapeutics.

I’ve heard a lot of futurists taking the angle that aging itself is a chronic disease. How do you feel about scientists that are approaching aging itself as a disease to be cured?  Is this a fool’s errand or an interesting approach?

I don’t think that aging itself is a disease. That being said, there are reasons to think that a traditional biomedical approach to curing diseases of aging may not have the impact we would like on adding disease free years at the end of life. A simplistic distinction between public health and medicine is the former is focused on prevention, the latter on cure. The success of a “disease-centric” approach to aging is limited by high levels of co-morbidities in the elderly—in the U.S. over half of people older than 65 have two or more chronic conditions. Curing one disease in its entirety does not add disease-free years to the end of life if other conditions remain. An alternative approach is applying a public health strategy, namely prevention, to basic science by reducing the extent to which age is a risk factor for disease. Potential for such an approach was first shown using the nematode C. elegans, where single gene mutations dramatically prolonged lifespan and maintained animals in a youthful state. Identical genetic modifications prolonged healthy lifespan in fruit flies, mouse, and have now been linked to long-lived human populations suggesting that, unlike chronological age, physiological age is malleable, and mechanisms that modulate it can be exploited to reduce overall disease risk. So, I do not think that studying the basic science of aging is a fools errand, it’s an alternative and complementary approach to discovery for disease therapeutics.

Obviously it’s hard to test whether this is the case in people, but I wonder whether you had any plans to? 

In our work we took advantage of the fact that C. elegans are transparent and used fluorescent reporters that allowed us to visualize splicing errors in live animals. We used these reporters to effectively predict which animals would live long and which would age faster. Of course in people this trick is not going to work! Instead, what we are working on is identifying specific RNA processing events that we can identify using molecular biology techniques, which give the same predictive power as the reporters. If funding allows we will extend this work to mammals to find conserved RNAs we might use as biomarkers of aging. These experiments are more expensive than those in C. elegans, which is why we need to support funding to the National Institutes of Aging—the average dollar contribution for each of us annually to the NIA is about $3.57—so for the price of one less coffee a year we could double our research investment into disease of aging!

As an expert in aging/longevity what are the top 5-10 lifestyle and health routines that you follow?

Personally my interests are in why aging exists and why it evolved, and how we can think about the aging process itself to design new therapeutics for age-onset diseases, rather than how we might prolong lifespan. So no dietary restriction for me! That said my lab works on a key energy sensor named AMPK that plays roles in DR and is activated by, amongst other things, exercise. So exercise and a whole food diet certainly mimics some of the interventions that slow aging in the lab.

Long term our goal is to develop therapeutics that might be used to reduce the extent to which age itself is a risk factor for chronic diseases. In just a hundred years we have added 25-30 years to average life expectancy in the US, with developing countries showing similar patterns. This trend is global and set to continue; by 2050 there will be 1.5 billion people over 65 worldwide. This rise in survival is overwhelmingly due to advances of public health, reducing childhood mortality and death from communicable diseases. However, success has come at a cost, as patient age is the single biggest risk factor for the majority of complex diseases. As a result, age-onset diseases including cancer, neurodegenerative diseases, type 2 diabetes and cardiovascular disease are generating a public health and economic burden that is rapidly becoming insurmountable. So our goal is to understand what it is that goes wrong in our cells in old age that leads to disease risk and find ways to prevent this occurring.

Science AMA Series: Hi, reddit! I’m Will Mair, assistant professor of genetics and complex diseases at Harvard T.H. Chan School of Public Health, and my lab recently found a causal link between RNA splicing and aging from science