Cognitive benefits of exercise may be driven in part by the hormone irisin

People who are physically active have reduced risks for cognitive decline, Alzheimer’s disease, and other dementias [1; 2]. Exercise improves cardiovascular and metabolic health, which improves overall health including brain health. But what is the biological mechanism through which exercise improves cognitive function? There are likely many, but recent laboratory studies suggest that the hormone irisin, which is secreted into the bloodstream during physical exercise, may play an important role [3; 4; 5]

What is irisin? Irisin was discovered in 2012 for its role in increasing energy expenditure from fat cells [6]. Since its discovery less than ten years ago, over a thousand studies have been published, evaluating the roles of irisin across different diseases, including metabolic disease, cardiovascular disease, kidney disease, atherosclerosis, and cancer. Irisin has also received attention as a potential novel drug target for Alzheimer’s disease. This is because a series of laboratory studies have demonstrated that in mice with Alzheimer’s-like pathology, boosting brain levels of irisin rescued memory function and increased a protein called BDNF that supports the growth and survival of brain cells [3; 4; 5]. In mice, endurance exercise using a free running wheel increased the levels of circulating irisin while also increasing irisin levels in the hippocampus, a brain region important for memory functions [5]. Mice lacking the gene that encodes irisin had impaired cognitive functions, but these deficits could be restored by treating these mice with irisin [3].

While no studies have tested irisin as an intervention for preventing Alzheimer’s disease or cognitive decline in humans, a few studies have examined the relationship between irisin levels and cognitive function. Compared to people without cognitive impairment, irisin levels in the spinal fluid (which bathes the brain) were significantly lower in people with late-stage Alzheimer’s disease as well as in those who had Lewy body dementia (a form of dementia where protein deposits called Lewy bodies damage brain cells) [4]. In an observational study that included Alzheimer’s patients and people without dementia, those who had higher irisin levels in the spinal fluid had higher cognitive function, higher BDNF levels, and lower amyloid deposits [7]. Thus, higher levels of irisin in the brain appear to be associated with better brain health.

As exciting and promising as irisin may be for cognitive health or dementia prevention, it is important to note that treatment with irisin or its derivatives have not been tested in humans yet, for any health condition. While higher circulating irisin levels have been associated with higher cognitive function, they have also been associated with harm in other conditions. For example, circulating irisin levels are increased in some cancers, obesity, and metabolic syndrome [8]. At this time, we are unable to rule out that some of these conditions could be worsened with an intervention involving irisin. Thus, irisin or its derivatives need to be carefully tested in preclinical studies and clinical trials before its safety is assured.

In the meantime, you can increase your irisin levels naturally by getting plenty of exercise. The World Health Organization recommends that adults get at least 150 minutes of moderate-intensity (or 75 minutes of vigorous-intensity) aerobic exercise every week, along with at least two days of muscle-strengthening activities [9]. In a study that compared different forms of exercises, high-intensity interval training (alternating short periods of intense anaerobic exercise with less intense recovery periods) increased irisin levels more than moderate-intensity continuous exercise [10].

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3. Islam MR, Valaris S, Young MF et al. (2021) Exercise hormone irisin is a critical regulator of cognitive function. Nature metabolism 3, 1058-1070.
4. Lourenco MV, Frozza RL, de Freitas GB et al. (2019) Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nature medicine 25, 165-175.
5. Wrann CD, White JP, Salogiannnis J et al. (2013) Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell metabolism 18, 649-659.
6. Bostrom P, Wu J, Jedrychowski MP et al. (2012) A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463-468.
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8. Askari H, Rajani SF, Poorebrahim M et al. (2018) A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: An introductory review. Pharmacological research 129, 44-55.
9. WHO (2020) Physical Activity.
10. Tsai CL, Pan CY, Tseng YT et al. (2021) Acute effects of high-intensity interval training and moderate-intensity continuous exercise on BDNF and irisin levels and neurocognitive performance in late middle-aged and older adults. Behavioural brain research 413, 113472.

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