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Epigenetic Testing: the Best Measurement for Biological Testing a Change in Philosophy About Longevity and Aging As a Disease

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Epigenetic Testing: the Best Measurement for Biological Testing a Change in Philosophy About Longevity and Aging As a Disease Epigenetic Testing: The Best Measurement for Biological Testing A Change in Philosophy about Longevity and Aging as a Disease The approach to Preventative Medicine has been limited due to little data and long periods of investigation. Now, there is a movement in medicine and in the community about longevity and the tools to fix this. Age now has an ICD-10 extension code! Why Do We Age? Aging is the time-dependent functional decline at the cellular level These 9 hallmarks of aging contribute to the aging process and determine one’s aging phenotype Aging is the loss of physiological integrity, this is the primary risk factor for major human pathologies, like cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases [Lopez-Otin et al 2013] Aging as a Risk Factor Aging is the greatest risk factor for a majority of chronic diseases. Collectively, chronic diseases comprise the majority of global disease burden and are the most common cause of mortality (kennedy et al. 2014) 80% of adults age 65+ have at least one chronic disease (NCOA) Percent of population 65+ with these common chronic conditions Hypertension (58%) High cholesterol (47%) Arthritis (31%) Coronary Heart Disease (29%) Diabetes (27%) Aging as a Risk Factor Aging causes the progressive damage of biological structures, contributing to the development of disease and death Members of the current generation of adults aged 45-64 live longer but are experiencing higher rates of chronic conditions By the time you reach 60, your risk of getting cancer doubles from when you were 50 (White et al. 2015) 70% of all cancers occur among adults aged 65 and up 82% of people who die from coronary heart disease are 65+ Aging as a Risk Factor Age is the predominant risk factor for many diseases, such as: Cardiovascular disease (North and Sinclair, 2012) Dementia (Querfurth and LaFerla, 2010) Osteoporosis (Raisz, 1988) Osteoarthritis (Raisz, 1988) Cancer (de Magalhães, 2013) Type 2 diabetes (Gunasekaran and Gannon, 2011) Unlocking the ways to regulate the rate of aging will help prevent some of the most common morbidities in the world Inflammation and Its Link to Health “Inflammaging” Local inflammation is a vital immune response triggered by infection and injury. Inflammatory responses promote the destruction and clearance of viral and bacterial pathogens, and enhance wound healing. Proinflammatory cytokines attract immune cells to sites of infection or injury, activating them to respond to the insult. While acute, local inflammation is beneficial, chronic low grade inflammation may have detrimental health consequences. Inflammation is a robust and reliable predictor of all-cause mortality in older adults. C-reactive protein (CRP) and proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α) are prognostic for cardiovascular disease, type II diabetes, arthritis, osteoporosis, Alzheimer's disease, and periodontal disease (Ershler and Keller, 2000; Kiecolt-Glaser et al., 2002). More globally, chronic inflammation has been suggested as one key biological mechanism that may fuel declines in physical function leading to frailty, disability, and, ultimately, death (Ershler and Keller, 2000). Aging and Senescence: SASP: Functions Senescence-associated secretory phenotype (SASP) Since aging is the greatest risk factor for every disease, how can we appropriately measure it? Are there better methods than chronological age? Chronological age (CA) is a commonly used indicator for aging. However, life expectancy shows considerable variation among individuals with equal or similar CAs due to diversity in genotypes and in living habits and environments. A 50-year-old individual may have 60-year-old body functions, and many people look older or younger compared to others at the same CA (even in twins). Therefore, CA is not an optimal indicator for the aging progress. The History Of Biological Age Measurements During the past decades, extensive effort has been made to identify such aging biomarkers that, according to the stage-setting definition (Baker and Sprott, 1988), are “biological parameters of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age, than will chronological age”. Later on, the American Federation for Aging Research (AFAR) formulated the criteria for aging biomarkers as follows: 1. It must predict the rate of aging. In other words, it would tell exactly where a person is in their total life span. It must be a better predictor of life span than chronological age. 2. It must monitor a basic process that underlies the aging process, not the effects of disease. 3. It must be able to be tested repeatedly without harming the person. For example, a blood test or an imaging technique. 4. It must be something that works in humans and in laboratory animals, such as mice. This is so that it can be tested in lab animals before being validated in humans. However, to date, no such marker or marker combination has emerged. What Else Makes a Good Biological Age Clock? Recently, several new biomarkers for biological aging have come into play. They can be separated into molecular- (based on DNA, proteomics, RNA etc.) or phenotypic biomarkers of aging (clinical measures such as blood pressure, grip strength, lipids etc.). They should be markers that predict chronological age, or at least can separate “young” from “old”. They should also be associated with a normal aging phenotype or a non-communicable age-related disease independent of chronological age in humans. What Should Biological Age Be Used For? A biological age predictor could be defined as a biomarker correlated with chronological age (black line), which brings additive information in the risk assessments for age-related conditions on top of chronological age. Hence, adult individuals of the same chronological age could possess different risks for age-associated diseases as judged from their biological ages (x's in figure). Usually, the positive predictive value (red line) of a biological age predictor decreases from mid-life and onwards due to the increased biological heterogeneity at old age (confidence interval described by dashed lines increases at old age). Why is Biological Age Testing Important Individual Precision Medicine - How does ___ intervention affect YOU? Validating therapies which reduce this can show us in real time what reduces risk. We can predict disease early (IvyGene and OncoBlot) We can tease out the reason and links for aging The Most Common Test for Biological Age: Telomeres Telomeres: What does this tell us? All cells have have a finite replicative potential; it is predictable based on the length of telomere repeat DNA. Telomeres define the ends of chromosomes and function to preserve genome integrity; they are comprised of TTAGGG sequences that are bound by specialized proteins. Telomere length (TL) shortens during DNA replication and, at a critical threshold, the shortest telomere(s) activate a DNA damage response that signals cell death or a permanent cell cycle arrest, known as cellular senescence The observations in cultured cells, and the fact that TL shortens with aging, have led to a hypothesized role for telomere shortening in human aging and age-related disease; however, the short TL threshold that is clinically relevant for disease risk is not known, and whether TL measurement can influence treatment decisions in clinical settings has not been determined. The Most Common Test for Biological Age: Telomeres Since the number of cell replication in vivo increases with age, telomere length (TL) is negatively correlated with age of proliferating somatic cells. Meta-analysis of 124 cross-sectional studies and 5 longitudinal studies showed that the correlation between leukocyte telomere length (LTL) and age ranges between r=-0.295 and r=-0.338 across adults Inherited deficiencies where telomere analysis is used in clinical diagnosis and to guide treatment include bone marrow failure, dyskeratosis congenita, aplastic anemia, acute myeloid leukemia, immune deficiencies, and pulmonary fibrosis. What about preventing disease outside of these conditions? Is TL helpful? What do large-scale and meta-analysis studies say on associations between telomere length and age-associated traits? Women on average have longer telomeres than men. Hence, women have a lower biological age than men as judged from the telomere lengths. Although no meta-analysis on mortality has been reported yet, the association between short telomeres and increased mortality risk has been shown repeatedly in many studies (Needham et al., 2015; Bakaysa et al., 2007; Deelen et al., 2014) However, a meta-analysis on telomere length and overall cancer risk (23,379 cases and 68,792 controls) showed a null result, indicating that telomeres may play different roles for different cancers (Zhu et al., 2016). Telomeres have also been associated with many age-related traits such as cognition and physical function. However, studies, and even meta-analysis efforts, are often small with limited conclusions (Gardner et al., 2013). Technical bias in the measurement of telomere lengths may also contribute to the lack of consistent results. What about preventing disease outside of these conditions? Is TL helpful? Short telomeres were found to be risk factors for gastrointestinal, head and neck cancers only. Furthermore, short telomere length has been described as a risk factor for coronary heart disease as judged
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