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Paul Clayton

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Are You Sitting Comfortably?

Because I am. I am slouched far too comfortably in one of an endless series of airport lounges. Awash with jetlag, in Far Eastern limbo and 14 hours into a 35-hour multi-flight nightmare, I am very aware that I am currently deep in Sitting Disease territory. I know that this is gradually increasing my risk of diabetes, heart disease, cancer and dementia.

I know also that Sitting Disease (defined as metabolic syndrome and other ill-effects caused by an overly sedentary lifestyle) is, according to evidence generated by the substantial Aerobics Center Longitudinal Study, a greater threat to public health and mortality than smoking, heart disease and diabetes (1-4). 

In fact, Sitting Disease emerges as the 4th leading risk factor for global mortality, and is estimated to contribute to or cause 3.2 million deaths per year (5, 6).

We were designed, like all animals, to move. But thanks to human ingenuity, and a natural inclination to be seduced by labour-saving technology that dates back to our early years in the evolutionary crucible, before food security, we don’t, much, any more. In fact we have become astonishingly sedentary, and are in the process of becoming even more sedentary.

Between 2001 and 2016, the time that adolescents spent sitting down increased from an average of 7.0 to 8.2 hours a day; while adults increased their sitting time from 5.5 to 6.4 hours a day (7). A significant part of this increase was due to time spent at computer or phone screens, reflecting the growing dominance of social media and content streamers.

The studies cited above show that Sitting Disease is killing far too many of us. Conversely, other research shows that taking regular exercise reduces the incidence of many cancers (8), diabetes (9) and dementia, even in the genetically predisposed (10). In short, it is life saving (11).

For example, one large cohort study (315 059 subjects) found that maintaining physical activity from adolescence into later adulthood was associated with an up to 36% lower risk for all-cause mortality (12). This is highly significant, and a clarion call to those leaving school or college. Don’t give up regular exercise for trifles such as marriage, kids, a demanding job, the destruction of prospects and prosperity by our idiot politicians, and winter, which is now crashing in upon us. Times are going to be even harder soon, and retaining some degree of physical fitness may save your life, the lives of those close to you, and a lot of medical expenses besides.

The message for older serfs like me, who may have let things slip a bit, is that it is not too late to make a change. One of the most reassuring findings of this study was that even in those who were inactive as young adults, increasing physical activity later in life (between the ages of 40 to 61) was equally protective (12)

So how and why does Sitting Disease cause harm, and why is exercise so beneficial?

As any modern physiology textbook will tell you, a sedentary lifestyle adversely affects the AMPK-MTOR axis. This weakens muscle, sinew and bone, leads to sarcopenia, fat accumulation and insulin resistance, and pushes the metabolism towards metabolic syndrome. So far so bad; that’s all fairly obvious, and explains a good deal of the increased mortality associated with excessive sitting on your ass. The increased inflammatory stress caused by insulin resistance is a major contributor to the increased cancer risk, and the junk food diet associated with the uber-sedentary lifestyle kicks in here too. But how does sitting link to dementia?

A good deal of this is driven through the metabolic syndrome / Type 2 diabetes axis too. Diabetics are more at risk of dementia due to an increased risk of multiple cerebral infarct, as well as increased inflammation, glycemic stress and insulin resistance (13), and excessive and related amyloidogenesis in both the brain and the pancreatic islets (14); although the concept of Alzheimer’s as a primary amyloidosis is falling out of fashion (15).

This explains why exercise is generally protective. But does it protect everyone? What about those at increased genetic risk? Do genes trump lifestyle? If you have a risk-promoting gene, does that mean you have permission to drop out of gym class? In a word – no. 

A research group at the University of Wisconsin School of Medicine and Public Health has been looking at this nexus for most of the last decade, and have concluded from their work that even in older subjects with a family history of Alzheimer’s Disease (AD), raised levels of physical activity reduces biomarkers for AD, and preserves memory and cognitive functioning (ie 16, 17). This is in line with the findings of scientists at the University of Exeter Medical School (UK), who also found that healthy lifestyle factors, including exercise and diet, provided significant protection against dementia and Alzheimer’s (18).

For those who have had their genes mapped and have a personal interest in this research, the level of activity found to be protective involved light workouts 5 days a week. For step counters, the data suggest that around 7500 steps/day (close to the 10,000 steps commonly recommended, so round up) may give maximal benefits (11).

Earlier, slightly Calvinistic theories held that exercise reduced health risks merely by promoting weight loss, with consequent changes in levels of sex steroids, insulin, insulin-like growth factors and adipokines (19). More recent evidence however shows that exercise exerts protective effects in overweight and obese subjects also (8), and activation of the AMPK-MTOR axis is surely involved. But there is more.

It turns out that walking conveys more than the general benefits of exercise. The leg bone may be connected to the hipbone, but leg muscles are connected directly to the brain.

The act of using these muscles triggers the synthesis and release in the brain of brain-derived neurotrophic factor (BDNF), a related increase in hippocampal neurogenesis (15, 20), and improved mood (21, 22).

This helps to explain why patients with motor neuron disease, multiple sclerosis, spinal muscular atrophy and other neurological diseases often rapidly decline when their movement becomes limited. It also implies that walking is supremely good and in fact necessary for brain health, justifying (if it needs any justification) ‘Mens sana in corpore sano’.

Thinking off my feet, sprawled in a China Eastern club armchair and lost in translation, comes an image of Charleses Darwin and Dickens walking and talking together in the late Victorian dusk, negotiating the difficult and painful passage from traditional religious conservatism towards the beautiful emergent complexity of science-driven materialism (23).

Both authors specialized in richly connected thinking and did much of their mental work while walking; although they reportedly walked at very different speeds. 

References:

1. Farrell SW, Kampert JB, Kohl HW 3rd, Barlow CE, Macera CA, Paffenbarger RS Jr, Gibbons LW, Blair SN. Influences of cardiorespiratory fitness levels and other predictors on cardiovascular disease mortality in men. Med Sci Sports Exerc. 1998 Jun;30(6):899-905.

2. Blair SN, Kampert JB, Kohl HW 3rd, Barlow CE, Macera CA, PaffenbargerRS Jr, Gibbons LW. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996 Jul 17;276(3):205-10.

3. Blair SN, Kohl HW 3rd, Barlow CE, Paffenbarger RS Jr, Gibbons LW, Macera CA.

Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA. 1995 Apr 12;273(14):1093-8.

4. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA. 1989 Nov 3;262(17):2395-401.

5. Stofan JRDiPietro LDavis DKohl HW 3rdBlair SN. Physical activity patterns associated with cardiorespiratory fitness and reduced mortality: the Aerobics Center Longitudinal Study. Am J Public Health. 1998 Dec;88(12):1807-13.

6. Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. JAMA Netw Open. 2018;1(6):e183605.

7. 7. Yang L, Cao C, Kantor ED, Nguyen LH,  Zheng X, Park Y, Giovannucci EL, Matthews CE,  Colditz GA, Cao Y. Trends in Sedentary Behavior Among the US Population, 2001-2016 JAMA. 2019;321(16):1587-1597. 

8. Moore SCLee IMWeiderpass ECampbell PTSampson JNKitahara CM, Keadle SK, Arem HBerrington de Gonzalez AHartge PAdami HOBlair CKBorch KBBoyd ECheck DPFournier AFreedman NDGunter MJohannson MKhaw KTLinet MSOrsini NPark YRiboli ERobien KSchairer CSesso HSpriggs MVan Dusen RWolk AMatthews CEPatel AV. Association of Leisure Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. JAMA Intern Med. 2016 Jun 1;176(6):816-25. 

9. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, Chasan-Taber L, Albright AL, Braun B; American College of Sports Medicine; American Diabetes Association. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care. 2010 Dec;33(12):e147-67.

10. Lourida I, Hannon E, Littlejohns TJ, Langa KM,, Hyppönen E,,Kuźma E, Llewellyn DJ, Association of Lifestyle and Genetic Risk With Incidence of Dementia JAMA. Published online July 14, 2019. doi:10.1001/jama.2019.9879

11. Lee I-M, MBBS,  Shiroma EJ, Kamada M, Bassett DR, Matthews CE, Buring JE. Association of Step Volume and Intensity With All-Cause Mortality in Older Women JAMA Intern Med. 2019;179(8):1105-1112.

12. Saint-Maurice PF, Coughlan D, Kelly SP, Keadle SK, Cook MB, Carlson SA, Fulton JE, Matthews CE. Association of Leisure-Time Physical Activity Across the Adult Life Course With All-Cause and Cause-Specific Mortality. JAMA Netw Open. 2019;2(3):e190355. 

13. .Soto M, Cai W, Konishi M, Kahn CR. Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6379-6384.

14. Wijesekara N, Ahrens R, Sabale M, Wu L, Ha K, Verdile G, Fraser PE. Amyloid-β and islet amyloid pathologies link Alzheimer’s disease and type 2 diabetes in a transgenic model. FASEB J. 2017 Dec;31(12):5409-5418.

15. Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science. 2018 Sep 7;361(6406). pii: eaan8821.

16. Tarumi T, Rossetti H, Thomas BP, Harris T, Tseng BY, Turner M, Wang C, German Z, Martin-Cook K, Stowe AM, Womack KB, Mathews D, Kerwin DR, Hynan L, Diaz-Arrastia R, Lu H, Cullum CM, Zhang R (Handling Associate Editor: Ozioma Okonkwo)Exercise Training in Amnestic Mild Cognitive Impairment: A One-Year Randomized Controlled Trial.

17.Dougherty RJSchultz SAKirby TKBoots EAOh JMEdwards DGallagher CLCarlsson CMBendlin BBAsthana SSager MAHermann BPChristian BTJohnson SCCook DBOkonkwo OC. Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer’s Disease. J Alzheimers Dis. 2017;58(4):1089-1097. 

18.Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hyppönen E, Kuzma E, Llewellyn DJ. Association of Lifestyle and Genetic Risk With Incidence of Dementia. JAMA. 2019 Jul 14. doi: 10.1001/jama.2019.9879.

19.Friedenreich CM, Neilson HK, Lynch BM.  State of the epidemiological evidence on physical activity and cancer prevention.  Eur J Cancer. 2010;46(14):2593-2604. 

20.Adami R, Pagano J, Colombo M, Platonova N, Recchia D, Chiaramonte R, Bottinelli R, Canepari M, Bottai D. Reduction of Movement in Neurological Diseases: Effects on Neural Stem Cells Characteristics. Front Neurosci. 2018 May 23;12:336.

21.Castrén E, Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis. 2017 Jan;97(Pt B):119-126.

22.Choi KW, Chen C-Y, Stein MB, Klimentidis YC, Wang M-J, Koenen KC, Smoller JW; for the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization StudyJAMA Psychiatry. 2019; 76(4):399-408. 

23. All the Year Round, Vol. 3 (1860): 174-77 and 293-299

This text was originally published here on Friday, August 30, 2019.
This is a guest post. The opinions expressed are the writer’s own.

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