Sergio PecorelliGiovanni Lorenzini Medical Foundation, Milan-New York

University of Brescia, Italy

sergio.pecorelli@lorenzinnifoundation.orgsergio.pecorelli@unibs.it

Muscat, February 14-17, 2020

The First 1000 days of LifeThe 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

19

50

19

60

19

70

19

80

19

90

20

00

20

10

20

20

20

30

20

40

20

50

20

60

20

70

20

80

20

90

21

00

Percentage of di >65 on the total population

8,0010,0012,0014,0016,0018,0020,0022,0024,0026,0028,00

19

50

- 1

95

5

19

60

- 1

96

5

19

70

- 1

97

5

19

80

- 1

98

5

19

90

- 1

99

5

20

00

- 2

00

5

20

10

- 2

01

5

20

20

- 2

02

5

20

30

- 2

03

5

20

40

- 2

04

5

20

50

- 2

05

5

20

60

- 2

06

5

20

70

- 2

07

5

20

80

- 2

08

5

20

90

- 2

09

5

Life Expectancy at 65 years

Africa

Asia

Europe

North America

Source: United Nations DESA. World Population

Prospects

Age 60+

868m12% Of World

Population

Age 60+

1.3b16% Of World

Population

Age 60+

2.03b21%

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 AmericaSource: United Nations DESA. World Population

Prospects

Changes in demographics

Chronic diseases and conditions

2 Emerging trends in healthcare

The increase of NCDs Worldwide

0

2

4

6

8

10

12

2000 2005 2010 2015 2020 2025 2030

De

ath

s (

mil

lio

ns

)D

ea

ths

in m

illi

on

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 NCDINHERITED AND ACQUIRED NCDs SUSCEPTIBILITY

No Physical activityPoor diet

Tobacco use

3 Behaviours

of deathsworldwide

50 Percent

CancerType 2 diabetes

Cardiovascular diseaseLung disease

4 Diseases

A simple equation

of Premature (<70 yrs) deathsworldwide

80 Percent

Pre-

mature

Death

High-level

Wellness

Treatment Paradigm

Wellness paradigm

Disability Symptoms Signs Awareness Education Growth

Illness-Wellness Continuum

52%of world

population

5%of 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 HealthThe incomining (necessary) transition

Diagnosis and treatment

Prediction and p

revention

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.

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

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 outcomes 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 duringdevelopment. They allow environmental influences to ‘tune the match’ of the organism to

its expected environment beyond that achieved through natural selection (i.e. inheritedgenotype).

DEVELOPMENTAL PLASTICITY

Life course

Ris

k

PlasticityDetrimental effects of lifestyle

challenges/increasing mismatch

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

Developmental Origins of Health and Diseases (DOHaD)

Preconception

Fetal life Adolescence Adult lifeInfancy 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

EXERCISE • 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

EXERCISE

• 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

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.

EXERCISE

• 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 spermDNA methylation.

• Global and genome-wide sperm DNA methylation is altered after threemonths of exercise training.

• DNA methylation changes occurred in genes related to numerous diseasessuch as schizophrenia and Parkinson’s disease.

• The same holds also for obesity and diabetes; in fact, sedentary menaffect the future fetus by exposing him or her to higher possibility ofbecoming 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 8weeks, normalized glucose intolerance in high-fat diet individuals.

• Physical exercise should start at least 180 days before conception (2 roundsof 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 disorganizedMII spindles remained present.

• Therefore, exercise is able to improve, but not reverse, damage imparted on oocytes 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.

NUTRITION 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

NUTRITION

• 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).243-254Hanson 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

other 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, endothelinsystem, 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 open 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 Sen1998 Nobel Laureate Economics

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

Amartya Sen1998 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

!