At the Mass General Research Institute, our community of 9,500+ investigators work diligently to publish peer-reviewed work and scientific findings to better understand disease and develop solutions to medicine’s most pressing challenges.

Footnotes in Science is a space where investigators bring you the behind-the-scenes details of their recently published work.

In this Q&A we pick the brain of Emiliano Santarnecchi, PhD, senior author of a recent review published in Ageing Research Reviews by Turrini et al., The multifactorial nature of healthy brain ageing: Brain changes, functional decline and protective factors

Dr. Santarnecchi is the Director of the Precision Neuroscience & Neuromodulation Program and the Director of the Network Control Laboratory within the Gordon Center for Medical Imaging at Massachusetts General Hospital. He is an Associate Professor of Radiology at Harvard Medical School.

What motivated you and your team to publish this study?

When approaching the literature on ageing, much of the available evidence focuses on individuals affected by various conditions leading to abnormal cognitive decline or individuals with an exceptionally positive ageing outcome (so-called SuperAgers).

Our goal was, instead, to put together the evidence on usual healthy brain and cognitive ageing, which we define as the composite pattern of modifications the human brain physiologically endures with advancing age, from the anatomical, functional and cognitive standpoint, when adequate typical functional ability and adaptability are retained.

We would like to promote a view of aging as a physiological process that should be embraced, focusing on Brain Health and ways to enhance it throughout the lifespan.

Can you expand on the mechanisms underlying healthy brain aging?

The outcome of our literature review is that the ageing process, even when healthy, determines a variety of modifications from the micro-scale level to the macro-scale.

Cellular level modifications include well-established hallmarks of cellular ageing, ranging from genomic instability to inflammation.

Meso-scale modifications involve the changes impacting the intercellular or local circuitry level, while macro-scale changes interest cortico-cortical networks, or the entire brain.

Interestingly, many of these changes, such as amyloid deposition, plasticity impairment, tau accumulation or network connectivity modifications, are shared with neurodegenerative diseases like Alzheimer’s.

However, they manifest with lower severity in healthy aging, placing healthy and pathological aging at the extremes of a thought-provoking continuum.

The mechanisms we describe are many, but we hope that having a clearer and more comprehensive picture of the cascade of modifications endured by the brain during the whole aging process can foster new studies and innovative perspectives on how to promote and support brain health into old age.

What are some modifiable risk factors to support a healthy aging process?

Multiple factors contribute to increase the risk of aggravating cognitive decline. Smoking, being affected by sleep disorders, excessive alcohol consumption, high-stress levels, social isolation or physical inactivity are some of the ones we discuss in our study, which could be counteracted by virtuous lifestyle changes or other interventions directly targeting altered brain networks such as noninvasive brain stimulation.

What are some potential effective interventions and protective strategies to promote cognitive reserve?

The World Health Organization defines healthy aging as “the process of developing and maintaining the functional ability that enables well-being in older age.”

Under this definition, healthy ageing is a “process,” a goal achieved throughout the lifespan to ensure the best possible outcome for one’s later years.

The main takeaway of our work should be that aging is a process that begins way earlier than one’s later years, and that reducing the risk of cognitive impairment would ideally mean adopting lifelong strategies and behaviors.

“It is never too early to start taking care of your brain”