Sergio Pecorelli Giovanni Lorenzini Medical Foundation, Milan-New - - PowerPoint PPT Presentation

Sergio Pecorelli

Giovanni Lorenzini Medical Foundation, Milan-New York University of Brescia, Italy sergio.pecorelli@lorenzinnifoundation.org sergio.pecorelli@unibs.it Muscat, February 14-17, 2020

The First 1000 days of Life

The early prevention of Non Communicable Diseases

Changes in demographics

2 Emerging trends in healthcare

Demographic Transition 1950 - 2100

0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0

1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 2060 2070 2080 2090 2100

Percentage of di >65 on the total population

8,00 10,00 12,00 14,00 16,00 18,00 20,00 22,00 24,00 26,00 28,00

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

Life Expectancy at 65 years

Africa

Asia Europe North America

Source: United Nations DESA. World Population Prospects

Age 60+

868m 12%

Of World Population Age 60+

1.3b 16%

Of World Population

Age 60+

2.03b 21%

Of World Population

2015 2030 2050 The Ageing Population

World’s Fertility Projection 1950 - 2100

0,00 1,00 2,00 3,00 4,00 5,00 6,00 7,00 8,00

Total Fertility (Children/Woman)

Africa

Asia Europa Nord America

Source: United Nations DESA. World Population Prospects

Changes in demographics Chronic diseases and conditions

2 Emerging trends in healthcare

The increase of NCDs Worldwide

2 4 6 8 10 12 2000 2005 2010 2015 2020 2025 2030 Deaths (millions) Deaths in million

Cancer

Heart Diseases Brain & Vascular Diseases Acute Respiratory Infections Perinatal Conditions

HIV/AIDS

Road deaths Tubercolosis Malaria

Environment

Genomics

Inherited traits

NCDs

Epigenetics Microbiome Metabolomics Psychosocial stressors

Exposures

INHERITED AND ACQUIRED NCD INHERITED AND ACQUIRED NCDs SUSCEPTIBILITY

No Physical activity Poor diet Tobacco use

3 Behaviours

• f deaths

worldwide

50 Percent

Cancer Type 2 diabetes Cardiovascular disease Lung disease

4 Diseases

A simple equation

• f Premature (<70

yrs) deaths worldwide

80 Percent

Pre- mature Death High-level Wellness

Treatment Paradigm Wellness paradigm

Disability Symptoms Signs Awareness Education Growth

Illness-Wellness Continuum

52%

• f world

population

5%

• f world

population

Neutral point (no discernable illness or wellness)

A sustainable healthcare system is possible yet imperative

Early prevention and lifestyle interventions (nutrition, physical exercise, anti-stressors…) are cost effective strategies to improve quality of life and hinder disease onset

1

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 sustainable healthcare system is possible yet imperative

2

Precision Medicine Precision Health

A new Approach to Health The incomining (necessary) transition

Diagnosis and treatment

Prediction and p revention Decentralization

• f 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

• f F1 through to F4 generations. This has been proven in rodents

and in many instances also in humans.

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

• f the fetus and term-offspring born with a

low birth mass. 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).

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

• utcomes including obesity and impaired

glucose tolerance (Hales and Barker 1992).

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. A REVOLUTIONARY THEORY: DOHaD

Barker D., 2003

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 PLASTICITY

Life course Risk Plasticity

Detrimental effects of lifestyle challenges/increasing mismatch

The first1000days of human development, including preconception and pregnancy phases, account for 70% of individual future health.

Developmental Origins of Health and Diseases (DOHaD)

Preconception

Fetal life Adolescence Adult life Infancy and childhood

Genetic susceptibility Cumulative incidence

Pre-conception

Chronic disease prevention: a life course approach

Older ages

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

EXE EXERCIS CISE

• There is an emerging evidence to show that physical activity

influences DNA methylation, histone modifications and regulation of noncoding RNA-associated genes in humans.

• 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

EXE EXERCIS CISE

• If the pregnant woman practiced diet and exercise, these

interventions were effecting and ameliorating the heritable metabolic consequences of paternal obesity and sedentary life.

• Therefore, paternal obesity was associated with the

transmission of metabolic syndrome risk factors to the

• ffspring, 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

• ffspring with increased hippocampal BDNF and reeling mi-

RNA and protein expression.

EXE EXERCIS CISE

• Interestingly the human fetus’s heart may be responsive to

maternal exercise, as maternal physical activity is positively correlated to fetal heart rate and the duration of activity was 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.

• 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
• f spermatogenesis).

Denham J. et al., Epigenomics 2015 Aug; 7 (5):717-31

Pre-conception and Physical Activity

The Sperm

Preconception

Paternal obesity and undernutrition

▪ Reduced sperm motility, increased DNA damage ▪ Altered sperm epigenome and RNA profile ▪ Altered seminal plasma composition ▪ Reduced embryo potential ▪ Epigenetic and reprogramming ▪ Endocrine misregulation ▪ Postnatal cardiometabolic disease risk

Preconception

• In females, the root of the decline in fertility is highly linked to

problems in the oocyte.

• These problems correlate with increasing BMI (and obesity), but also

with undernutrition. The Oocyte

Preconception

Maternal obesity and overnutrition

• Metabolite and lipid accumulation in follicles and eggs
• Mitochondrial damage Metabolite and lipid accumulation in

follicles and eggs

• Cellular and ER stress
• Epigenetic and metabolic reprogramming
• Postnatal cardiometabolic disease risk
• Adverse programming evident after embryo transfer

Preconception

Maternal undernutrition

• Metabolite and lipid accumulation in follicles and eggs
• Mitochondrial damage Metabolite and lipid accumulation in

follicles and eggs

• Cellular and ER stress
• Epigenetic and metabolic reprogramming
• Postnatal cardiometabolic disease risk
• Adverse programming evident after embryo transfer

Preconception

• In mice, physical exercise can improve lipid metabolism in germinal vesicle

(GV) stage oocytes, by a significant increased activity and transcription of the β-oxidation enzyme hydroxyacyl-coenzyme A dehydrogenase, only if the mice had been fed a high-fat diet (HFD).

• An exercise intervention also reversed the lipid accumulation seen in GV

stage oocytes of HFD females. However, delays in meiosis and disorganized MII spindles remained present.

• Therefore, exercise is able to improve, but not reverse, damage imparted on
• ocytes as a result of a HFD and obesity.

Boudoures AL et al., Reproduction 2016 Mar; 151(3):261-70

Oocyte and Physical Exercise

Oocyte Maturation

• Optimal maturation of the oocyte depends on its environment and

determines embryo competence

• the embryonic genome is not active until the cleavage stage and new

mitochondria are not produced until blastulation.

• Adverse environmental factors include aging, oxidative stress, obesity,

smoking, alcohol, and psychological stress.

• A prudent diet, physical exercise, nutritional supplements, and

psychological interventions have beneficial effects.

• Mitochondrial function and energy production deteriorate with age,

adversely affecting ovarian reserve, chromosome segregation, and embryo competence.

Oocyte Maturation

• Early human experience has been encouraging.
• Mitochondrial metabolic stress can result in an abnormal compensatory

increase in mitochondrial DNA, which can be assessed in biopsied blastomeres of trophectoderm as a predictive biomarker of implantation failure.

• Psychological stress may reduce oocyte competence by shifting blood flow

away from the ovary as part of the classic "fight or flight" physiologic response.

• Methods to reduce stress or the body's reaction to stress improve pregnancy

success.

• Physical exercise represents the most important method.
• Enhancing oocyte competence is a key intervention that promises to reduce

the number of euploid embryos failing to produce viable deliveries.

NUTRITI NUTRITION ON

Environmental factors (primarily nutrion) condition the Metabolic Programming (MP)

• CVDs (CardioVascularDiseases) and Metabolic disorders prevention

means following nutrition rules, starting since early life

Barker D: J Intern Med 2007; 261:412-417 Weintraub WS et al. Circulation 2011,124:967-990

NUTRITI NUTRITION ON

• Metabolic Programming (MP) creates new “preferential”

metabolic pathways; it is more efficient in early life (early life programming) from conception through adolescence.

• MP takes place through epigenetic processes (mainly histone

remodeling) in germ cells (pre-conception) and in the embryo/fetus.

• Epigenetic changes may be transmitted to next generations

Ravi Nistala et al. Cardiorenal Med 2011;1(4).243-254 Hanson MA et al. Ann Nutr Metab 2011; 58:8-15 Barker DJ J Intern Med 2007;261:412-417

HEART DISEASE

• Decreased Cardiomyocytes Numbers
• Adverse Ventricular and Subcellular Remodeling
• Cardiac Fibrosis
• Myocardial Hypoplasia
• Cardiac Contractile Abnormalities
• Activation of Hypoxia Inducible Factor
• Dysregulation of Angiogenesis
• Mitochondrial Abnormalities
• DNA, Protein & Lipid Oxidation
• Altered Glucose & Fatty Acid Transport &

metabolism

• Deregulation of the HPA Axis/Cortisol regulation
• Alterations in the RAS (Renin-Angiotensin System)
• Increase/Decrease Nutrient Transport
• Increase/Decrease Cortisol Transfer
• Increase in Oxidative Stress
• Maternal Undernutrition/Overnutrition
• Maternal Obesity/Diabetes/Sedentary Life
• Maternal Stress
• Advanced Maternal Age
• Placental insufficiency
• High Altitude Pregnancies
• Pre-conception
• Paternal obesity
• Sedentary life

The Developmental Origin of Heart diseases

➢ This study focuses on lifestyle improvement and the effects of this lifestyle improvement in the period between preconception and 1 year post partum. ➢ The effects of an unhealthy lifestyle in this period can impact health of the entire lifespan

New discoveries in EPIGENETICS will stimulate a change in the understanding and implementation of knowledge and attitudes regarding conception, pregnancy, child’s and adult’s health. Many present beliefs will need to be critically revised with deep social impact

Conclusive “Take Home Messages” (1)

➢ Physical exercise of the father (even if obese) and of the mother in the pre-conception period is important for the epigenetics of germ cells (sperm & oocytes) and of the mother during pregnancy to prevent metabolic and

• ther chronic diseases in future offspring.

➢ The embryo-fetal placental development is a plastic process where a single genotype can express many different phenotypes. Developmental processes from genotype to phenotype occur in a contest dependent and in a sex specific way ➢ Excessive stressors may not only affect the fetal survival possibilities and increase the risk of pathological outcomes of pregnancy but also may increase the disease risk and the disease susceptibility during the lifetime and may act on the lifespan itself.

Conclusive “Take Home Messages” (2)

➢ The adaptation to stress in the developing fetus is a complex process where many mechanisms are involved and integrated with one other; there is a substantial agreement that the main biological systems that mediate adaptation to stress are the maternal-placental-fetal neuroendocrine and immune systems; these systems act in a sex- specific way. ➢ Glucocorticoids are an important switch driving the gene regulation changes in fetal normal growth and maturation. Fetal exposure to glucocorticoids excess induces disruption in organ developments producing smaller organs or altered organ morphology and functions, influencing lifelong health and diseases

Conclusive “Take Home Messages” (3)

➢ The cascade of mechanisms activated in the fetal developmental programming as genic expression, DNA methylation and epigenetic way, telomere and mithocondrial biology just like many systems as the sympathetic nervous system, the renin angiotensin system, the mother- placenta-fetal immune-tolerance system, oxidative stress, endothelin system, inflammatory cytokines, act in a sex specific way.

Perspectives

➢The increasing body of scientific evidence about fetal programming confirms the “developmental origin of health and disease” in fetal life and also the presence of sex specific differences. ➢The numerous studies on the mechanisms how an environmental context may produce one or other phenotype

• pen broad research horizons.

➢All this may translate into incredible benefits to Society in Health, Wellness and healthcare sustainability. ➢Educational programs should be implemented

“Poor prenatal experience sows the seeds of ailments that afflict adults.”

Amartya Sen

1998 Nobel Laureate Economics

“The womb is a promising target for prevention, both in high and low resources countries.”

Amartya Sen

1998 Nobel Laureate Economics

DIMENSION OF HEALTH AND WELLNESS

Spiritual Social

Health and wellness are a multi-dimensional entangled universe

Emotional- mental Intellectual Physical

The first 1000 days of life youtube: https://youtu.be/eyrG_EFd4-k

TED Talk

Giovanni Lorenzini Medical Foundation

Thank you !