Over the past 50 years, health care hasn’t slowed the aging process so much as it has slowed the dying process.

ADVS 6800Mahdi Nazokkar Maher

How Diet and Reproductive Function Influence the Decline of Health at Older Ages

Life Span

122 years59 years

Maximum life span

3 years

Pinus longaeva (Bristlecone pine) ~5000 years

 Life Span is the amount of time between the birth and death of a person, plant or animal

Jeanne Calment

Health Span

• The period of a person's life during, which are generally healthy and free from serious or chronic illness health span

• Health span is a part of life span

Life SpanHealth Span

Diet Restriction Reproductive FunctionDiseases

Human Diseases

(Brian J. North 2012)

Diseases can reduce health span

• Cardiovascular• Diabetes• Alzheimer• Arthritis

DiseasesH SL S

Diabetes

• Diabetes is a disease in which blood glucose, or blood sugar, is not well controlled by body.

• Type 1 diabetes is a chronic condition in which the pancreas produces little or no insulin.

• Genetics and exposure to certain viruses such as enteroviruses may contribute to type 1 diabetes

• With type 2 diabetes, the body either does not respond to insulin or does not produce enough insulin.

• QI .L (2009): Western dietary patterns can increase the risk of type 2 diabetes.

Diabetes in Humans

(Shugang Li (2015))

Diabetes in Animals

• In a diabetic animal, the pancreas is unable to secrete enough (or any) insulin to allow the glucose to leave the bloodstream

• Dietary restriction influences on diabetes

• Dogs are most often found to have type 1 diabetes

• Insulin resistance is present in equine Cushing's disease

• Cats have a combination of type 1 and 2

Dietary RestrictionKatewa. S. D (2009):• Dietary restriction (DR) can increase active and healthy

life and health span in a variety of species• Dietary restriction (DR) is a reduction of specific or total

nutrient intake • Dietary restriction can be based on protein, lipid,

carbohydrate or caloric restrictions. • A positive relationship between DR and life and health

span is demonstrated in various organisms including yeast, worms, flies, mice, monkeys and humans

(Center for Environmental and Molecular )

A Relationship between Dietary Restriction and Health

Span

Insulin Signaling Pathway

Dietary Restriction

Life Span Health Span

Dietary Restriction in Worms

Schulz . J.T (2007): Increasing cellular glucose

is a fundamental concept in treatment of type 2 diabetes

Dietary restriction based on glucose reduction extends the life and health span

Dietary Restriction in Flys

Cooper . T. M. (2004):• Restriction of diet

increases life and health span.

Dietary Restriction in Mice

Sun. L (2009)

• Life span and health span can be extended in rodents by restricting food

Dietary Restriction in Monkeys

Colman . R. J. (2014):• DR significantly improves age-

related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood

• Ramsey. J. J (2000):Wisconsin Research Center (WNPRC), improved longevity associated with 30% DR in monkeys

• Mattison. J. A( 2012): the National Institute on Aging (NIA)DR has not improved longevity outcomes in monkeys.

• Three studies: DR improved health span in all the studies

Dietary Restriction in Worms, Flies and Mice

Dietary Restriction

Insulin pathway

Life span

Daf-16 (FOXO)

Dietary Restriction

Insulin pathway

dFOXO

Life span

Dietary Restriction

Insulin pathway

FOXO

Life span

Insulin Signaling Pathway

Mungenast, F. (2014):

• High levels of inulin signaling increase the translocation of FOXO protein from the nucleus to the cytoplasm

http://www.cisreg.ca/cgi-bin/tfe/articles.pl?tfid=478

Foxo Family Genes

• FOXO’s are important in human, mouse, fly and worm life span.

• Willcox. D. C (2010): The FOXO3A gene is important to healthy aging and longevity in human

• Maiese K (2007): FOXO3's decrease oxidative stress

• Mutations in FOXO family genes can decrease ovarian function in mice

(Wen-Hung Chung (2010))

Mutation in FOX Genes Disrupts Ovarian Function in Mice

Hosaka. T (2003):

• Benayoun et al., 2008 : Mutation FOXL2 plays a crucial role in ovarian development and female fertility in mice and fish

• Hosaka. T (2003): Mutation FOXO3a disrupted follicle maturation• Yong Yu. (2014): FOXO1 influences in somatic cells differentiation.

At 12 weeks , Foxo3a -/- ovaries had no developing follicles

• FOXL2 is required to prevent transdifferentiation of an adult ovary to a testis

• In the absence of SRY or SOX9 function the gonad develops as an ovary

Uhlenhaut N. H. (2009):

Germ Cell Depletion Extends Life Span in Worms

• Germ cells are depleted by using Laser ablations

Hsin, H. (1999): • Germ line depletion

increases life span• When the somatic

gonad is ablated, lifespan is not extended

• Somatic cells play essential role in life span extension in worms

Life Span in Worms

Dietary Restriction Germ Cell Depletion

DR

IIS

Daf-16(FOXO)

Life Span(Hsin, H. (1999))

Germ Cell Depletion Extends Life Span in Flies

Flatt, T. (2008): • Depletion of germ cells (GCs)

increases life span

• Germ-line-less flies show increased activation Drosophila FOXO (dFOXO)

• Life span is increased in fly by just depletion of germ cells not depletion of somatic cells

• bag of marbles (bam) is necessary and sufficient for differentiation of

GCs. Ectopic misexpression of bam + by using heat shock-induction, lead to deplete the GCs

Life Span in Fly

Dietary Restriction Germ Cell Depletion

Germ Cell Depletions

InsulinPathway

dFOXO

Life Span

Dietary Restriction

InsulinPathway

dFOXO

Life Span

Foxo in Humans Soerensen. M. (2010): • Genetic variations of FOXO genes influence human longevity

• Foxo3a gene variants are more common in centenarians compared to the general population. These variants are significant for survival from younger ages to old age, yet not during old age.

• Japanese-Americans in Hawaii [B. J. Willcox. 2008]• German and French [F. Flachsbart. 2009]• Italian populations [C. V. Anselmi. 2009]• Han Chinese population [Yang Li. 2009]• Danish population [Soerensen. M. 2010]

FOXO3a2100 years

L FFOXO3a1 FOXO3a2

Gender Influences Health Span

What is the difference between female and male disease rates?

Yang Li(2009):

• FOXO1A is associated with female longevity while FOXO3A is associated with longevity in both genders in humans

• Genetic contributions to longevity traits may be affected by gender

Gender is a Significant Factor on Disease RatesWhat is the difference between female and male disease rates?

Menopause

Menopause• The time in a woman's life when menstrual periods

permanently stop

• Loss of ovarian activity

• Change in germ cell and somatic cell function

• Life span in the post-menopausal state – 1/3 to 1/2

Gender Has a Significant Influence on Disease RatesOvarian Protective Effect

Menopause

Ovarian Activity Decreases

Disease Rates

Increased Health with Decreased Ovarian

Activity ?

Disease Rates

Transplantation of young ovaries to post-reproductive mice increased life span

and decreased cardiomyopathy.

0.00

0.20

0.40

0.60

0.80

1.00

Sham Sx New Ovary

P = 0.005

Evidence of Cardiomyopathy at Death

Mean age at death in sham surgery mice (non-transplanted) = 722 days

Mean age at death in non-cycling, young ovary transplant recipients = 811 days

IT

ITS

IT-TXIT-S ITT

IT-TX

Increasing reproductive life span increased health and

chronological life span

In Conclusion

IIS GC

SC

DR

FOXO

Health SpanLife Span

In Conclusion Mammals?

IIS

GC SC DR

FOXO

Health SpanLife Span

Take Home Message

• Dietary restriction can positively regulate insulin signaling

• Dietary restriction can increase health span • FOXO’s are critical mediators of insulin/IGF-1 signaling• Reproductive function can influence health span• Germ cell depletion increases life span in worms and

flies• FOXO3a variants are associated with longevity in both

genders in humans• Mutation of FOX family genes decrease ovarian

function

Questions