Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - HIIT AGEING (The impact of High Intensity Interval Training on inflammatory state and immune function in elderly individuals)

Although life expectancy is increasing, the disparity between maximal lifespan and maximal time spent healthy is also increasing. This expanding gap not only diminishes quality of life in the elderly but creates a substantial economic burden on health resources. A major factor contributing to poor health in old age is the increase in systemic inflammation, termed inflammaging. As such, increased systemic inflammation is believed to be a causative factor in cardiovascular disease, type-2 diabetes, dementia and some cancers. Importantly, if inflammation is a key driver of so many age-related morbidities, then tackling this process could have a profound impact on health in old age.

The etiology of inflammaging is associated with increased obesity, physical inactivity and an age-related decline in immune function, termed immunosenescence. Each factor is interlinked with physical inactivity promoting obesity; adipocytes produce inflammatory cytokines and adipokines which impair the function of the immune system and augment inflammation leading to local tissue damage including smooth and skeletal muscle limiting physical activity. As these factors are interlinked and do not operate in isolation there is potential to modify inflammaging by promoting physical activity and/or reducing adiposity.

Physical activity and structured exercise have anti-inflammatory effects through modification of adipose tissue and immune function. However, elderly individuals are much less inclined to engage in physical activity, with time and intensity of exercise participation significantly reduced. Common barriers to exercise participation in the elderly are a ‘lack of knowledge’ and a ‘lack of time’ as many have active social lives or care for ill partners and/or grandchildren. Recent evidence suggests that when compared to longer-duration continuous moderate intensity exercise (MICT), adoption of a short-duration higher intensity interval (HIT) based exercise program may elicit similar physiological benefits. HIT training reduces time commitment by around 50% and as such there are increased adherence rates compared to MICT. Therefore, implementation in an elderly cohort (over 65 years) may offer significant health improvements at a reduced time expenditure and potentially reduce the risk of age-related morbidities such as CVD, diabetes and Alzheimer’s disease.

The primary aim of this project was to elucidate the effect of a novel exercise intervention (HIT) on the inflammatory status, immune function and health indicators in older adults and in patients with inflammatory disease. The research sought to achieve this through 4 main objectives. Participants would complete a ten-week structured supervised HIT exercise training program and be assessed for inflammatory and immune responses (RO1), broader physiological and cognitive functions (RO2), intervention efficacy in clinical populations with chronic inflammatory conditions (RO3) and characterization of the response of the metabolome and determine interactions with immune and inflammation changes to assess potential mechanisms (RO4).

To-date the study has completed 22 adults who were tested at baseline and following 10-weeks of supervised exercise training. Exercise training, consisted of 3 x 30-minute walking sessions per week consisting of a 5-minute warm-up and 5-minute cool-down and a set of higher intensity intervals interspersed with lower intensity intervals. Intervals consisted of 60 – 90 seconds walking at a workload corresponding to a heart rate reserve for 80 – 90% VO2peak and for the lower intensities, 50 – 60% VO2peak. Typical workloads were between 2 and 4 mph and gradients of 3 to 15% and were relative to each individual’s fitness capacity. Ten participants (HIIT-PD), consisting of four men and six women who were relatively healthy but were at risk of developing type-2 diabetes. Twelve participants (HIIT-RA), consisting of eleven women and one man had confirmed rheumatoid arthritis. Recruitment into the HIIT-PD study was limited by the number of age-appropriate participants with prediabetes living close enough to the university who were able and willing to take part in the study. As such, we approached a total of twenty participants with only ten taking part and completing the study. This limitation was recognized prior to recruitment for the HIIT-RA study. Here, we approached the physicians in the Rheumatology Department at Duke Hospital and the Veterinary Affairs Hospital in Durham. Following a database search (DEDUCE) of suitable candidates it was recognized that there were very few over 65-year-old patients living in close proximity to the University with RA. Therefore, we made the decision to lower the inclusion age to 55 years old. Our DEDUCE search identified 384 participants, and 86 study letters/invites were sent out to those who lived within 30 miles of the University. Although we completed 12 participants, more could have been done with more time and resources.

Main Results
Physiological Adaptations to the Training: Cardiorespiratory fitness (CRF) improved significantly by approximately 16% in the HIIT-PD and 8% in the HIIT-RA study. CRF improvements included increases in maximal absolute amounts of oxygen utilized (VO2peak: L/min) and relative VO2peak: mL/min/kg. As absolute VO2peak was improved this suggests improvements in cardiac function were evident and thus improved cardiac output and stroke volume which is indicative of reduced risk of cardiovascular disease. These findings are reinforced by no changes in spirometry measured lung assessment of forced vital capacity and forced expiratory volume. To put these results into perspective the Duke team led by Prof. Kraus observed similar CRF improvements in participants with prediabetes who completed 26 weeks of 3 x 45-60 minute sessions of continuous aerobic exercise at a workload corresponding to 75% VO2peak. Therefore, our exercise paradigm elicited similar CRF results in 20% of the total exercise time commitment as previous studies at a lower exercise intensity.
As the exercise bouts were short, caloric expenditure was minimal and therefore there was no apparent changes in body composition. Body weight, BMI, waist and hip circumference, fat mass and lean mass were unchanged in both studies, although non-significant, the trend was for the HIIT-PD participants to loose fat mass and the HIIT-RA participants to gain fat mass. These results highlight the need for some form of caloric restriction in those taking part in HIIT training if weight loss is an outcome goal. Although there were no changes for seated blood pressure or resting heart rate in the HIIT-PD study, but there were trends (p<0.07) for reduced systolic and diastolic blood pressure and a significant reduction in resting heart rate in the HIIT-RA participants. As such there were no changes in peripheral arterial compliance or blood flow velocity as measured by pulse wave tonometry in either group. Kidney function as measured by urinalysis was unaffected by the intervention.

Physical functioning is reduced with age due to physical inactivity and exposure to systemic inflammation which increases the risks for falls and frailty. As expected, arm strength did not change, however leg strength as measured by isokinetic dynamometry and 30-second chair stands improved in both studies. As such there were trends for improved balance (BBS), daily walk speed (TUG) and both groups significantly improved 400m walk time suggesting improved muscle tone and function in the lower extremities in the absence of increased muscle mass.

Disease Specific Changes: Glucose tolerance and insulin sensitivity as measured by a 3-hour oral glucose tolerance test, were significantly improved in the HIIT-PD while a trend for lower HbA1c was evident suggesting a reduced risk of developing diabetes. The Disease Activity Score-28 (DAS-28) which incorporates measures of swollen and tender joints, self-perceived global health and plasma inflammation as measured by erythrocyte sedimentation rates indicated a 4% reduction in disease activity for the HIIT-RA group. This change in the DAS-28 is better reflected by a clinical change from moderate disease activity to low disease activity.

Immunological Measures: Total white blood cell (WBC) counts and WBC differentials are a surrogate marker for health status and inflammation. Baseline results were unremarkable and thus no changes were observed for either group. Neutrophils were isolated from the blood and functional assays completed, including migration, pathogen killing (ROS), pathogen ingestion (phagocytosis), cell surface receptor expression and mitochondrial function. Significant improvements were observed in both groups for migration, pathogenic killing and ingestion and mitochondrial function but no changes were observed for cell surface expression related to functional improvements. These results suggest an anti-inflammatory immune response which is promotes enhanced pathogen clearance and is indicative of reduced risk of infectious episodes.

Future: Taken together our findings so far suggest that HIIT in clinical populations is safe, tolerable and highly effective at improving immunological, inflammatory and physiological functions. We have frozen cell samples, plasma and other biological samples including muscle biopsies. Biopsies from HIIT-PD have been assessed by microarray and data is being disseminated now. HIIT-RA samples will be sent later this year and again assessed by microarray. Plasma and urine samples are being prepared for analyses of inflammatory cytokines and growth factors and cell samples further quantified for function and aging phenotype (telomere length). Finally, we have a large amount of cognitive questionnaires which are being assessed at present. Data has been presented at two international conferences and has been submitted for presentation at 2 more conferences in 2017. Manuscripts are under preparation and will be submitted later this year, however Dr. Bartlett has published one manuscript with the group at Duke and has another under review.

Expected Final Results and Impact: Results so far have developed our understanding of novel exercise prescriptions and can be applied to different clinical populations (e.g. geriatrics, rheumatology, endocrinology etc.). As such I have been invited to contribute to the US Governments Physical Activity Guidelines Advisory Committee under the Subcommittee of Dose Response Recommendations. The work to be conducted at Birmingham will be the first to determine mechanisms by which HIT training is improving function so well. Results will undoubtedly have an impact in clinical exercise prescription by offering new guidance to physicians about specific exercise responses required for varying conditions.

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