Sit Less, Move More to Induce Irisin and Stave Off Dementia

Physical activity staves off dementia, but does that mean being sedentary makes cognitive decline more likely? Yes, according to David Raichlen, University of Southern California, Los Angeles, and colleagues. In the September 12 JAMA, the scientists reported that, among almost 50,000 people, being inactive for 15 hours per day tripled dementia risk over seven years compared to the group's average of nine hours of sitting a day.

“Sitting all day long deteriorates pretty much all biological systems in the body, including the brain,” wrote Borja del Pozo Cruz, University of Southern Denmark in Odense, to Alzforum (comment below).

The study implies that exercise benefits the brain. “Moving and engaging in physical activities as much as possible is very important for physical and cognitive health in old age,” wrote Kumar Rajan, Rush University, Chicago.

Exactly how might exercise protect the brain? On this separate but related research question, scientists led by Rudolph Tanzi and Se Hoon Choi at Massachusetts General Hospital, Charlestown, offered a molecular mechanism pointing to protection from the effects of brain amyloid deposition. In the September 8 Neuron, they reported that the exercise-induced hormone irisin reduces soluble Aβ in vitro by binding to integrin receptors on astrocytes, which prompted release of the Aβ protease neprilysin.

Previously, Raichlen and others had found that certain self-reported sedentary behaviors, such as watching TV, raised the risk of future dementia (Raichlen et al., 2022; Bakrania et al., 2018). However, a more recent study led by Steve Nguyen, University of California San Diego, La Jolla, of almost 1,300 women who wore accelerometers to track their activity reported no such link (Nguyen et al., 2023).

To conduct a larger data-driven study that goes beyond self-reporting by collecting physical activity data, first author Raichlen analyzed accelerometer and clinical data from 49,841 cognitively normal U.K. Biobank participants aged 60 and older. Fifty-four percent were women; 97 percent were white. Participants wore an activity tracker on their wrists 24 hours a day for three days to a week, then were followed for an average of seven years to see who developed all-cause dementia; 414 did.

The scientists used a previously developed machine-learning algorithm to decipher when people were sedentary or active. They had trained the algorithm to identify 30-second bouts as active or not based on annotated accelerometer data from 152 U.K. Biobank participants who also donned a wearable camera and kept a time diary (Walmsley et al., 2021). 

The new study showed that people sat for about nine hours a day, on average. Sitting for 12 hours per day increased all-cause dementia risk by 63 percent, while sitting for 15 hours came with a whopping 3.2-fold higher risk.

“The size of the study, the mean length of follow-up, and the careful statistical analyses covarying for usual demographic factors make the findings plausible,” wrote Henry Brodaty, University of New South Wales, Sydney. Nguyen agreed. “Higher sedentary behavior is associated with higher risk of cardiovascular disease, which, in turn, is associated with higher dementia risk,” he wrote (comments below).

This study suggests that getting off the couch helps maintain a sharp mind, adding to a growing body of evidence (Sep 2022 news; Aug 2021 news; Sep 2019 news).

Some research even suggests that physical activity may protect the brain from amyloid accumulation and its effects (Jul 2019 conference news). How could that be?

In their new paper, Tanzi and Choi implicate the Aβ endopeptidase neprilysin and the hormone irisin, both of which rise in the brain after exercise in mouse models of amyloidosis (Maesako et al., 2012; Moore et al., 2016; Oct 2013 news). Irisin protected the mice from synaptic and memory deficits (Jan 2019 news).

To see if irisin and neprilysin interact, first author Eunhee Kim and colleagues used three-dimensional co-cultures of human neurons, astrocytes, and oligodendrocytes, all carrying APP Swedish, APP London, and presenilin 1 ΔE9 mutations, that the group had previously developed (Oct 2014 news; Sep 2023 news). These cultures make copious amounts of Aβ and hyperphosphorylated tau. After treating 3.5-week-old three-dimensional cultures with irisin for 10 days, Kim saw fewer dystrophic neurites, measured less Aβ40, Aβ42, and phospho-tau in the media, and detected twice as much soluble neprilysin.

Co-treating with the neprilysin inhibitor sacubitril, a vasodilator used in clinical practice, ramped up soluble Aβ42 levels, suggesting that the enzyme is crucial to irisin’s amyloid-lowering ability. Sacubitril is a component of the heart failure drug Entresto, and has been shown to change patients' plasma Aβ42/40 ratio (Dec 2022 conference news).

From Exercise to Less Aβ? The exercise hormone Irisin (green circle) binds to integrin receptors αV and β5 on astrocytes, prompting a signaling cascade culminating in the secretion of neprilysin (secNEP), which degrades Aβ. [Courtesy of Kim, et al., Neuron, 2023.]

Since astrocytes make neprilysin, might irisin prompt them to pump out the enzyme? Indeed, when Kim tested this hunch by applying irisin to human iPSC-derived astrocytes, they released neprilysin. In the three-dimensional cultures, Kim spotted astrocytes highly expressing integrin β5, an irisin receptor in bone and fat cells, suggesting this may be how the hormone acts on these brain cells too (Kim et al., 2018). 

In the cultures, irisin activated this integrin receptor, as evidenced by increased phosphorylation of its downstream signaling proteins. Blocking integrin β5, either by treating with an inhibitor or knocking down its gene, prevented irisin from lowering soluble Aβ42 and raising neprilysin expression.

To the authors, these results mean that irisin binds the integrin receptor on astrocytes, stirring them to release neprilysin and degrade Aβ (see image above). “This beautiful study adds insight into the neuroprotective mechanisms of irisin in Alzheimer’s experimental models,” wrote Fernanda De Felice of Queen's University, Ontario, Canada (comment below).—Chelsea Weidman Burke

Comments

  1. The U.K. Biobank study findings are stronger than what the Women's Health Initiative Memory Study/Objective Physical Activity and Cardiovascular Health in Older Women, aka WHIMS/OPACH, study showed. In OPACH, higher total sitting time and longer mean sitting bout durations were not associated with higher dementia risk. Differences in study findings between the U.K. Biobank and the WHIMS/OPACH could be due to differences in study population characteristics, what particular activity monitor was used, and where it was worn on the body, and how dementia was classified.

    In OPACH, the mean age was 81.8 + 6.2 years, whereas in the U.K. Biobank the median age for those with incident dementia was 71 (IQR=68-74) and 67 (IQR=64-70) for those without incident dementia, so the U.K. Biobank study population was not yet old enough to observe higher dementia rates.  Additionally, OPACH women wore the well-known research grade ActiGraph GT3X+ , which is worn around the hip, as opposed to a wrist-worn device, and sedentary behavior was classified using a novel and validated machine-learned algorithm that captures postural transitions more accurately than traditional accelerometer data-processing methods. Importantly, dementia diagnosis in the WHIMS/OPACH involved careful annual cognitive assessments over time and adjudication using several sources of neurocognitive data and a panel of experts, as opposed to clinical diagnoses in the medical record.

    Physical functioning was not accounted for in analyses, which could distort the relationship between sedentary behavior and dementia. Individuals with lower physical functioning might accumulate more sedentary behavior, have less physical activity, and could have health conditions not captured in the other study variables, or be at higher risk of developing health conditions, resulting in higher dementia risk.

    Nonetheless, the findings from this rigorous and thorough U.K. Biobank study are plausible and relevant, as higher sedentary behavior is associated with higher risk of cardiovascular disease, which in turn is associated with higher dementia risk. The results are also consistent with current evidence-based guidelines recommending that individuals reduce their sedentary time.

    The take-home is that given there are few if any risks of adverse outcomes with reducing sedentary behavior, it seems prudent to encourage individuals to sit less and move more.

    View all comments by Steve Nguyen

  2. This paper can be used to better counsel patients on how lifestyle choices and dementia risk are related. In my opinion, the main strength of this study is a very large sample size, which enables the authors to control for many co-variates at once, e.g., age, sex, education, ApoE, Townsend score, chronic conditions, etc. Having this sort of statistical power and ability to account for covariates is rare, and lends credence to the conclusions they draw.

    The lack of significantly increased risk in Quartile 3 (9.27h to 10.44 h/d) suggests that there may be substantial improvement in risk conferred by modestly decreasing the amount of one’s sedentary behavior, i.e., moving from Q4 to 3.

    I would have liked more discussion of device-measured sleep in the paper. While the overall n is high, at 49,841, the number of incident dementia cases was fairly low, at 414 incident dementia cases, <1 percent. ... Perhaps that’s due to the relatively young age? This might impact the generalizability of the results.

    View all comments by Jasmeer Chhatwal

  3. In this retrospective study, more sedentary behaviours were associated with an increased risk of dementia. The size of the study, the main length of follow up (6.72 years), and the careful statistical analyses covarying for usual demographic factors, exercise, diet, sleep, chronic health conditions, smoking, alcohol use, body mass index, APOE E4 make the findings plausible.

    Further, the possibility of reverse causality was lessened by the authors’ use of landmark analysis, whereby people who developed a dementia diagnosis within four years of accelerometer recording were excluded. There was a dose effect, although at the very high end of sedentary behaviour, numbers were small and confidence intervals wide.

    The mechanism for the association is not clear. Chronic health conditions, which were controlled for, were based on physician diagnosis of vascular or heart disease including myocardial infarct, angina, stroke or current high blood pressure, diabetes, or cancer. There were many limitations to the study, which require caution in interpreting the results.

    View all comments by Henry Brodaty

  4. To me these findings are not surprising at all. Sitting all day long deteriorates pretty much all biological system in the body, including the brain. It is likely that most of these cases are related to vascular dementia, hence the observed effects with inactivity. The main take-home message is that one should break sitting time and replace it with some active time to counteract the negative effects of too much sitting.

    View all comments by Borja del Pozo Cruz

  5. In this study, the authors investigated how irisin could affect Aβ pathology in Alzheimer’s disease. They report that irisin treatment causes a reduction in Aβ pathology by stimulating increased neprilysin release from astrocytes. Additional analysis revealed that increased neprilysin release from astrocytes by irisin is mediated through ERK-STAT3 signaling. The results also suggest that irisin’s effects on astrocytes occur through integrin aV/b5 receptors. Another interesting finding is that irisin significantly reduced gene expression levels of the astrocyte reactivity markers, implying that irisin could potentially help restrain the activity of reactive astrocytes known to contribute to AD pathogenesis. 

    Overall, the results are exciting, and the in vitro experiments were well done and analyzed appropriately. The results suggest irisin treatment could reduce Aβ plaques in amyloidosis or AD.

    The entire study was performed in three-dimenesional cultures of REN cells expressing FAD-associated mutations. While the reported results from three-dimenesional cultures are valuable and provide mechanistic insights, it remains to be determined whether similar results could be obtained through systemic or localized irisin administration into brain regions in mouse models of amyloidosis or AD.

    Three-dimenesional cultures in the study were maintained with recombinant irisin protein for 1.5 weeks, which could be considered a continuous long-term exposure. Providing such continuous exposure to irisin in the brain will be challenging. Future studies need to determine whether intermittent irisin treatment commencing in the early stage of the disease would be sufficient to reduce Aβ plaques long-term.

    View all comments by Ashok Shetty

  6. This is a beautiful study that adds insight into the neuroprotective mechanisms of irisin in Alzheimer’s experimental models. In my opinion, the main takeaway of this study is that irisin triggers the release of neprilysin by binding integrins on astrocytes. This explains how irisin may decrease Aβ levels in 3D cultures, as observed by authors. 

    The release of neprilysin by irisin is an important contribution to the field. It is in harmony with our findings showing that recombinant irisin reduced the binding of Aβ oligomers to neurons and that FNDC5/irisin overexpression reduced hippocampal soluble Aβ42 levels in APP/PS1 M146L mice (Lourenco et al., 2019).

    In our study, we further observed that surface FNDC5/irisin and Aβ oligomers did not colocalize in dendrites of hippocampal neurons, which can be explained by the current study showing that irisin acts on astrocytes.

    References:

    Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Gonçalves RA, Clarke JR, Beckman D, Staniszewski A, Berman H, Guerra LA, Forny-Germano L, Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF, Prado MA, Abisambra JF, Tovar-Moll F, Mattos P, Arancio O, Ferreira ST, De Felice FG. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med. 2019 Jan;25(1):165-175. Epub 2019 Jan 7 PubMed.

    View all comments by Fernanda De Felice

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References

News Citations

  1. Can 10,000 Steps a Day Keep Dementia at Bay?
  2. Can Exercise Protect People Whose Plasma Tau Is Up?
  3. 'Runner Plasma' Jogs Neurogenesis, Quells Neuroinflammation in Mice
  4. Physical Activity May Shield the Brain from the Onslaught of Aβ
  5. Does Peripheral Hormone Control Expression of Brain Trophic Factor?
  6. Could the Purported Muscle Exercise Hormone, Irisin, Jog Memory?
  7. Alzheimer’s in a Dish? Aβ Stokes Tau Pathology in Third Dimension
  8. In 3D Cell Model of AD, Microglia and CD8+ T Cells Gang Up on Neurons
  9. Blood Amyloid Test May Help Diagnose Alzheimer’s, but Questions Remain

Mutations Citations

  1. APP K670_M671delinsNL (Swedish)
  2. APP V717I (London)
  3. PSEN1 c.869-22_869-23ins18 (ΔE9)

Paper Citations

  1. Raichlen DA, Klimentidis YC, Sayre MK, Bharadwaj PK, Lai MH, Wilcox RR, Alexander GE. Leisure-time sedentary behaviors are differentially associated with all-cause dementia regardless of engagement in physical activity. Proc Natl Acad Sci U S A. 2022 Aug 30;119(35):e2206931119. Epub 2022 Aug 22 PubMed.
  2. Bakrania K, Edwardson CL, Khunti K, Bandelow S, Davies MJ, Yates T. Associations Between Sedentary Behaviors and Cognitive Function: Cross-Sectional and Prospective Findings From the UK Biobank. Am J Epidemiol. 2018 Mar 1;187(3):441-454. PubMed.
  3. Nguyen S, LaCroix AZ, Hayden KM, Di C, Palta P, Stefanick ML, Manson JE, Rapp SR, LaMonte MJ, Bellettiere J. Accelerometer-measured physical activity and sitting with incident mild cognitive impairment or probable dementia among older women. Alzheimers Dement. 2023 Jan 25; PubMed.
  4. Walmsley R, Chan S, Smith-Byrne K, Ramakrishnan R, Woodward M, Rahimi K, Dwyer T, Bennett D, Doherty A. Reallocation of time between device-measured movement behaviours and risk of incident cardiovascular disease. Br J Sports Med. 2021 Sep 6;56(18):1008-17. PubMed.
  5. Maesako M, Uemura K, Kubota M, Kuzuya A, Sasaki K, Hayashida N, Asada-Utsugi M, Watanabe K, Uemura M, Kihara T, Takahashi R, Shimohama S, Kinoshita A. Exercise Is More Effective than Diet Control in Preventing High Fat Diet-induced β-Amyloid Deposition and Memory Deficit in Amyloid Precursor Protein Transgenic Mice. J Biol Chem. 2012 Jun 29;287(27):23024-33. PubMed.
  6. Moore KM, Girens RE, Larson SK, Jones MR, Restivo JL, Holtzman DM, Cirrito JR, Yuede CM, Zimmerman SD, Timson BF. A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer's disease. Neurobiol Dis. 2016 Jan;85:218-24. Epub 2015 Nov 10 PubMed.
  7. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM. Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell. 2018 Dec 13;175(7):1756-1768.e17. PubMed.

Further Reading

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Primary Papers

  1. Raichlen DA, Aslan DH, Sayre MK, Bharadwaj PK, Ally M, Maltagliati S, Lai MH, Wilcox RR, Klimentidis YC, Alexander GE. Sedentary Behavior and Incident Dementia Among Older Adults. JAMA. 2023 Sep 12;330(10):934-940. PubMed.
  2. Kim E, Kim H, Jedrychowski MP, Bakiasi G, Park J, Kruskop J, Choi Y, Kwak SS, Quinti L, Kim DY, Wrann CD, Spiegelman BM, Tanzi RE, Choi SH. Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron. 2023 Nov 15;111(22):3619-3633.e8. Epub 2023 Sep 8 PubMed.

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