HES 383 - Physical Dimensions of Aging PDF

HES 383 – PHYSICAL DIMENSIONS OF AGING Sept 6th 2024 Healthspan vs Lifespan, Cellular Mechanisms of Aging, Strategies to Delay Aging Prof Gina Whitaker, BSc Kin, PhD The UBC Okanagan Campus and the City of Kelowna are locat...

HES 383 – PHYSICAL DIMENSIONS OF AGING Sept 6th 2024 Healthspan vs Lifespan, Cellular Mechanisms of Aging, Strategies to Delay Aging Prof Gina Whitaker, BSc Kin, PhD The UBC Okanagan Campus and the City of Kelowna are located on the traditional, ancestral, and unceded territory of the Syilx Okanagan Nation. Our life expectancy has increased, but does this mean that we will just spend more years in poor functional health? Hearing loss, vision loss Osteoarthritis Frailty Cancer incidence is on the rise Cognitive Decline & Dementia Sarcopenia Cardiovascular diseases are a huge burden on the health care system Isolation, loneliness, depression Multimorbidity incidence is on the rise  FUNCTIONAL HEALTH DECLINES WITH AGE Functional health, in this case, is determined using a scoring system based on self-reported performance on 8 key health attributes Vision Hearing Speech Mobility Dexterity Feelings Cognition Pain Yves Decady and Lawson Greenberg. 2014. “Ninety years of change in life expectancy” Health at a Glance. July. Statistics Canada Catalogue no. 82-624-X. “No 60 year old – even the healthiest, hardest-training, and most disease-free 60 years old – can sprint as fast or throw as far as could a healthy 25 year old.” This is evidence that aging, the progressive decline in physical function that accompanies growing older, occurs even in the absence of disease  LIFESPAN VS HEALTHSPAN: THE HEALTH- ADJUSTED LIFE EXPECTANCY (HALE) Determine HALE (or healthspan) by calculating the number of years an individual is expected to live in good functional health  HALE in Canada: - 69 YO for men - 71 YO for women Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001 2024 SO, WE HAVE ADDED YEARS TO LIFE, BUT HAVE WE ADDED LIFE TO YEARS?? Results from studies show that we have made some small steps toward increased healthspan, but we are still spending roughly the same percent of life in poor health. Conclusions from Stats Canada Life expectancy and HALE study: “Life expectancy and HALE have increased over time in Canada. The gap between males and females has narrowed because of greater gains by males during the past 20 years. The ratio of HALE to life expectancy has remained stable, which suggests neither a reduction nor improvement in overall functional health relative to life expectancy. Mobility problems and pain, the latter mainly among females, now account for a greater percentage of the burden of ill health.” Retrieved from: https://www150.statcan.gc.ca/n1/pub/82-003-x/2018004/article/54950-eng.htm  THE HEALTH REVOLUTION Finding strategies to compress morbidity in order to extend healthspan Fig 1 (To live long, AND well) Seals DR, et. al. Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity. (2016) Journal of Physiology 54.8 2001-2024  STRATEGIES TO PREVENT FUNCTIONAL DECLINE Primary prevention Delay onset, reduce magnitude and/or prevent age-related decline of function Greatest potential to extend healthspan here, especially when prevention is applied over the lifespan Secondary prevention Strategies to improve function in individuals that are already experiencing some decline in function. Goal here is to prevent further decline, Fig 5 delay or prevent onset of chronic disease, or even improve function Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001 2024  CAN WE ACTUALLY SLOW AGING? Some cancers Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001 2024  BIOLOGICAL THEORIES OF AGING PROGRAMMED AGING DAMAGE/ERROR-BASED Our cells have an intrinsic biological Damage inside the cells builds up clock and are preprogramed to over time, eventually causing the cells function normally for only a specific to malfunction length of time, then they malfunction  Regardless of the theory, it is thought that aging is due to cellular dysfunction (lots of changes occurring inside the cells to cause this dysfunction – see next slide)  Cellular dysfunction leads to imbalance in homeostatic processes, eventually causing systemic malfunction  MOLECULAR & CELLULAR MECHANISMS OF AGING Genomic instability – DNA becomes more susceptible to mutations and damage Epigenetic modifications – gene expression gets turned on or off due to malfunctioning at the genomic level Telomere attrition – telomeres are the caps on the end of DNA. They get shorter with each DNA replication and eventually become critically short so the DNA can no longer replicate Impaired protein homeostasis – proteins in cells are no longer functioning properly due to misfolding Dysregulated energy (nutrient) sensing – impaired ability to sense and respond to changes in nutrient availability  metabolic dysfunction Mitochondrial dysfunction – function decreases and impairs cell metabolism, causes oxidative stress Cellular Senescence – cells get ‘old’ but instead of dying by apoptosis (programmed cell death), they are dysfunctional and also cause damage to cells around them Chronic Inflammation – low level of inflammation in the absence of infection Stem cell exhaustion – stem cells eventually start to die off and thus new cells can no longer be made  THE HALLMARKS OF AGING Ferrucci L, Gonzalez-Freire M, Fabbri E, Simonsick E, Tanaka T, Moore Z, Salimi S, Sierra F, de Cabo R. Measuring biological aging in humans: A quest. Aging Cell. 2020 Feb;19(2):e13080. doi: 10.1111/acel.13080.  Aging is BY FAR the biggest risk factor for all major chronic diseases Treating one chronic disease may not greatly impact life Some cancers expectancy because it will be swapped out for another disease or morbidity If we can slow the aging process down, then we would be able to delay the clinical manifestation of all these chronic diseases To do this, we need to target the cellular mechanisms of aging Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001 2024 Baar MP, Van Willigenburg H, de Keizer PLJ. Maintenance and repair of an aging life cycle. Oncotarget. 2017 May 21;8(50):86985-86986. doi: 10.18632/oncotarget.18046. PMID: 29152057; PMCID: PMC5675609.  ANTI-AGING STRATEGIES & THE HALLMARKS OF AGING THEY COUNTERACT Tenchov, R., Sasso, J. M., Wang, X., & Zhou, Q. A. (2024). Antiaging Strategies and Remedies: A Landscape of Research Progress and Promise. ACS chemical neuroscience, 15(3), 408–446. https://doi.org/10.1021/acschemneuro.3c00532  Primary prevention – Most effective to delay, decrease magnitude and / or prevent age-associated decline in function Secondary prevention – Improve function when physiological decline has already begun in order to delay or prevent onset of functional limitations, disability, disease Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001 2024 LIFESTYLE-BEHAVIOURAL STRATEGIES AS PREVENTION OF AGING Regular Physical Activity Healthy Dietary Practices Stress Management Conventional Preventive Medicine Practices get regular checkups & screening, vaccines, taking pills for high BP, etc. REGULAR, LIFELONG PHYSICAL ACTIVITY Strongest evidence of preservation of physiological function with aging Evidence across many research venues Animal models of aging Cross-sectional analyses comparing adults who are physically active to sedentary adults Longitudinal studies that observe functional status over a span of life Exercise intervention trials on older adults EVIDENCE FOR LONG-TERM PHYSICAL ACTIVITY RESULTING IN A DELAY IN FUNCTIONAL DECLINE Cross-sectional study The age at which decreases in cardiorespiratory fitness and muscle strength reach levels associated with frailty can be delayed by up to 30 years Lower aerobic and lower strength capacities are predictive of frailty, morbidity & mortality in older adults Frailty threshold is defined as VO2max < 18ml/kg/min Booth & Zwetsloot (2010). Basic concepts about genes, inactivity and aging. Scand J Med Sci Sports 20, 1-4  Longitudinal study (21 years) Participants were 50+ at study start Significant delay in developing disability and increased survival rates in runners vs. healthy controls Study participants were followed yearly by completing a questionnaire to assess their functional status (Mean disability score) The questionnaire assessed 8 basic functional tasks (rising, dressing and grooming, hygiene, eating, walking, reach, grip, routine physical activities) Researchers kept track of deaths as the study progressed Arch Intern Med. 2008;168(15):1638-1646. A BRIEF SUMMARY OF WHAT CELLULAR STUDIES HAVE SHOWN… Physical Exercise has been shown (at least in animal models) to have an anti-aging effect on all 10 cellular hallmarks of aging. Regular exercise decreases oxidative stress in our cells – exercise is an antioxidant Regular exercise decreases chronic low-grade inflammation throughout the body Regular exercise enhances mitochondrial health and function Regular exercise keeps our cells clean and smooth in their function – like a well-oiled machine Regular exercise helps maintain length of telomeres Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001-2024  SOME EVIDENCE SCIENCE DAILY NEWS - ARTICLE 1 SCIENCE DAILY NEWS – ARTICLE 2  Gives evidence for the following that can lengthen our telomeres: Managing chronic stress Exercising Eating better Getting enough sleep How much exercise? People who do moderate exercise 3x per week have telomeres similar in length to marathon runners Cross training is good: one study showed the more different kinds of exercise people did, the longer their telomeres were DIET – RESTRICTING ENERGY INTAKE Many studies done on rodents and primates– extreme lifelong caloric restriction (40% less than normal ad libitum feeding) Increases lifespan Delays or prevents physiological decline of cardiovascular system, neuromuscular system, cognitive function. Human studies Extreme caloric restriction is difficult to maintain long term Weight loss intervention studies on healthy normal weight-to-obese older adults have shown improved cardiovascular function, glucose-insulin regulation, memory and mobility. Intermittent fasting shows promise in anti-aging research CALORIC RESTRICTION IN RHESUS MONKEYS Monkeys on Calorie-restricted diet: Optimal body weight and composition Lower incidence of cancer Lower incidence of cardiovascular disease Better control of blood glucose levels Calorie-restricted Ad libidum  STUDY: MOUSE LEMURS & CALORIC RESTRICTION Typical lifespan: of the mouse lemur: Median survival in captivity of 5.7 years Max lifespan of 12 years In this study: median survival times were 6.4 and 9.6 years for control and calorie- restricted animals, respectively Corresponds to a 50% increase in median lifespan 73% of deaths were age- Pifferi, F., Terrien, J., Marchal, J. et al. Caloric restriction increases lifespan but related for control affects brain integrity in grey mouse lemur primates. Commun Biol 1, 30 (2018) 33% of deaths were age- doi:10.1038/s42003-018-0024-8 related for calorie- restricted group  INTERMITTENT FASTING TO SLOW AGING Intermittent fasting triggers AUTOPHAGY within your cells It is thought that AUTOPHAGY may also be cleaning up the cellular damage that tends to build up with aging Intermittent fasting also induces cellular stress resistance New research focus in intermittent fasting and longevity health benefits  All aging studies on animal models  Show improvement in life span  Magnitude of effect on lifespan extension is variable (influenced by sex, diet and genetics)  Disease-modifying effects shown (animal models) for obesity, type 2 diabetes, cardiovascular disease, cancers & neurodegenerative brain diseases  DIET COMPOSITION High in fruits & vegetables, whole grains, fish, nuts, oils E.g. Mediterranean diet or DASH diet Consumption of these diets is associated with positive functional and overall health profiles with aging  Anti-inflammatory  Antioxidant  Low fat / Good fat  Lower glycemic index NUTRACEUTICALS Foods or natural ingredients from food with potential health benefits that are beyond their basic nutritional value One well known and studied nutraceutical: Resveratrol: a polyphenol found in red wine and grapes - known to directly inhibit components of cell aging - studies suggest that supplementation could improve age-associated neuromuscular strength and endurance, blood glucose levels, and cardiovascular function - lots of resveratrol supplements on the market  NUTRACEUTIC AL: CURCUMIN (FOUND IN TURMERIC) Bielak-Zmijewska, A., Grabowska, W., Ciolko, A., Bojko, A., Mosieniak, G., Bijoch, Ł., & Sikora, E. (2019). The Role of Curcumin in the Modulation of Ageing. International journal of molecular sciences, 20(5), 1239. https://doi.org/10.3390/ijms20051239  AGING IS MULTIDIMENSIONAL Social, psychological and physiological influences of aging also likely target cellular mechanisms of aging (through the central nervous system or directly) Fig 8 Seals, D.R., Justice, J.N., LaRocca, T.L. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity (2016) J Physiol 594(8): 2001-2024