The First 1000 days of Life The early prevention of Non Communicable Diseases Muscat, February 14-17, 2020 Sergio Pecorelli Giovanni Lorenzini Medical Foundation, Milan-New York University of Brescia, Italy sergio.pecorelli@lorenzinnifoundation.org sergio.pecorelli@unibs.it
2 Emerging trends in healthcare Changes in demographics
Demographic Transition 1950 - 2100 Life Expectancy at 65 years Percentage of di >65 on the total population 28,00 35,0 26,00 24,00 30,0 22,00 20,00 25,0 18,00 16,00 20,0 14,00 12,00 15,0 10,00 8,00 10,0 1950 - 1955 1960 - 1965 1970 - 1975 1980 - 1985 1990 - 1995 2000 - 2005 2010 - 2015 2020 - 2025 2030 - 2035 2040 - 2045 2050 - 2055 2060 - 2065 2070 - 2075 2080 - 2085 2090 - 2095 5,0 0,0 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 2060 2070 2080 2090 2100 Africa Asia Europe Source: United Nations DESA. World Population North America Prospects
The Ageing Population 2050 Age 60+ 2030 2.03b 21% Age 60+ 2015 1.3b Of World Population Age 60+ 16% 868m Of World 12% Population Of World Population
World’s Fertility Projection 1950 - 2100 Total Fertility (Children/Woman) 8,00 7,00 6,00 5,00 4,00 3,00 2,00 1,00 0,00 Africa Asia Europa Nord America Source: United Nations DESA. World Population Prospects
2 Emerging trends in healthcare Changes in demographics Chronic diseases and conditions
The increase of NCDs Worldwide 12 Cancer 10 Heart Diseases Brain & Vascular Diseases Deaths (millions) Deaths in million 8 6 4 Acute Respiratory Infections Perinatal Conditions 2 HIV/AIDS Road deaths Tubercolosis Malaria 0 2000 2005 2010 2015 2020 2025 2030
INHERITED AND ACQUIRED NCDs SUSCEPTIBILITY INHERITED AND ACQUIRED NCD Genomics Inherited traits Epigenetics Microbiome NCDs Metabolomics Psychosocial stressors Exposures Environment
A simple equation 50 3 Behaviours 4 Percent Diseases Cancer No Physical activity Type 2 diabetes of deaths Poor diet Cardiovascular disease worldwide Tobacco use Lung disease 80 Percent of Premature (<70 yrs) deaths worldwide
Illness-Wellness Continuum 52% 5% of world of world population population Wellness paradigm Pre- High-level mature Wellness Disability Symptoms Signs Awareness Education Growth Death Treatment Paradigm Neutral point (no discernable illness or wellness)
A sustainable healthcare system is possible yet imperative 1 Early prevention and lifestyle interventions (nutrition, physical exercise, anti-stressors … ) are cost effective strategies to improve quality of life and hinder disease onset
A sustainable healthcare system is possible yet imperative 2 Empower individuals to correct behaviour and involve them in the technology development phase and usage (data sharing …) improving the sense of responsability and self-awareness
A new Approach to Health The incomining (necessary) transition Precision Precision Medicine Health Prediction and p revention Diagnosis and treatment Decentralization of care services
Trans-generational epigenetic inheritance of health or disease ➢ Current evidence indicates a role for environmentally induced alterations to epigenetic modifications leading to health and disease changes across multiple generations. ➢ This phenomenon is called intergenerational or trans-generational epigenetic inheritance of health or disease. ➢ Environmental insults perturb the epigenetic landscape and influence, from pre-conception to pregnancy and child, the health of F1 through to F4 generations. This has been proven in rodents and in many instances also in humans.
THE «BARKER HYPOTHESIS» Barker D., 1989, 1992 David Barker, looking at the 20th century epidemic of CVD in Western countries, postulated his hypothesis that impaired fetal growth (defined as <2.5 kg at birth) might predispose survivors to heart disease (coronary heart disease, hypertension, stroke and diabetes) in later life (Barker et al. 1989; Barker 1992). Maternal dietary inadequacies will lead to a decrease in nutrient supply to the developing fetus and, as a consequence, results in an impairment in the growth and development of the fetus and term-offspring born with a low birth mass.
THE «BARKER HYPOTHESIS» Barker D., 1989, 1992 The hypothesis has subsequently been modified to include a second component, and that is the idea of the “thrifty phenotype” that predicts that, as an adaptation to undernutrition in fetal life, where permanent metabolic and endocrine changes occur, such changes are considered to be beneficial as long as nutrition remains scarse after birth. However if nutrition becomes plentiful, these changes predispose to adverse health outcomes including obesity and impaired glucose tolerance (Hales and Barker 1992).
A REVOLUTIONARY THEORY: DOH a D Barker D., 2003 The Developmental Origins of Health and Disease (DOHaD) theory suggests that targeted interventions on early-life stages, including individual behavior, optimization of nutrition, physical activity, reduction of stress, noise exposure, monitoring of drugs and environmental pollutants, such as endocrine disruptors , are needed to tackle the increasing prevalence of NCDs. Since NCDs represent a substantial limit to main global issues such as poverty and sustainable development, the implementation of preventive interventions at local, regional, and international levels constitutes a critical mandate.
DEVELOPMENTAL PLASTICITY Developmental plasticity encompasses those processes that generate alternative phenotypes from a single genotype through the actions of environmental cues acting during development. They allow environmental influences to ‘ tune the match’ of the organism to its expected environment beyond that achieved through natural selection (i.e. inherited genotype).
Developmental Origins of Health and Diseases (DOHaD) The first1000days of human development, including preconception and pregnancy phases, account for 70% of Risk individual future health. Life course Plasticity Preconception Detrimental effects of lifestyle challenges/increasing mismatch
Chronic disease prevention: a life course approach Infancy and Pre-conception Fetal life Adolescence Adult life Older ages childhood Cumulative incidence Genetic susceptibility
Pre-conception Medicine Pre-conception medicine aims to identify and modify biomedical, behavioral and social risks through preventive interventions upon germ cells Physical activity Nutrition Stressors
• There is an emerging evidence to show that physical activity CISE EXERCIS influences DNA methylation, histone modifications and regulation of noncoding RNA-associated genes in humans. EXE • Accumulating evidence supports trans-generational inheritance of DNA methylation changes in mammals via germ cells. • Exercise training reprograms the sperm methylome, that augments transcriptional programs protective of disease, including metabolic dysfunction, heart disease, neuro- degeneration and cancer. Denham J et al.: Epigenomics 2015 Aug;7(5):717-31
CISE • If the pregnant woman practiced diet and exercise, these EXERCIS interventions were effecting and ameliorating the heritable metabolic consequences of paternal obesity and sedentary EXE life. • Therefore, paternal obesity was associated with the transmission of metabolic syndrome risk factors to the offspring, but maternal exercise was a successful intervention that prevented the harmful epigenetic inheritance of disease. • Regarding cognitive function, paternal exercise is associated with superior spatial learning and memory capacity in the offspring with increased hippocampal BDNF and reeling mi- RNA and protein expression.
CISE • Interestingly the human fetus’s heart may be responsive to EXERCIS maternal exercise, as maternal physical activity is positively correlated to fetal heart rate and the duration of activity was EXE negatively correlated to the heart rate variability. • Given marked impact of exercise on the heart transcriptome and miRNome, it is possible that epigenetic reprogramming is responsible for the reduced risk of offspring congenital heart disease risk and other cardiovascular outcomes.
Pre-conception and Physical Activity The Sperm • Exercise has been shown to determine an important effect on sperm DNA methylation. • Global and genome-wide sperm DNA methylation is altered after three months of exercise training. • DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson’s disease. • The same holds also for obesity and diabetes; in fact, sedentary men affect the future fetus by exposing him or her to higher possibility of becoming overweight, obese and possibly diabetic. Denham J. et al., Epigenomics 2015 Aug; 7 (5):717-31
Pre-conception and Physical Activity The Sperm • It has also been shown that pre-conception paternal exercise training attenuates the aberrant sperm mi-RNA and DNA methylation alterations associated with high-fat diet-induced obesity and metabolic dysfunction. • As an example, a pre-conception swimming exercise of at least 8 weeks, normalized glucose intolerance in high-fat diet individuals. • Physical exercise should start at least 180 days before conception (2 rounds of spermatogenesis). Denham J. et al., Epigenomics 2015 Aug; 7 (5):717-31
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