The use of mitochondrial nutrients to improve IVF. Robert F Casper MD

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1 The use of mitochondrial nutrients to improve IVF Robert F Casper MD

2 Reproductive Aging Women in the developed world are delaying childbirth for many reasons In the last 10 years, first births for: Women years old increased by 36% Women years old increased by 70%

3 Female Aging Pregnancy rate decreases Miscarriage rate increases Decreased ovarian reserve Increased oocyte and embryo aneuploidy

4 Trisomy 21 & maternal age

5 To date there is no known intervention to improve oocyte quality, pregnancy rates and outcome in older patients.

6 Hypothesis Oocyte mitochondrial dysfunction has a major role in reproductive senescence The oocyte has approx 200,000 mitochondria Oocyte ATP only source of energy for meiosis and for embryo cleavage up to the blastocyst stage

7 Oocyte Mitochondria and Aging Increased maternal age is accompanied by: Increased mtdna mutations Changes in mitochondrial function Altered metabolic activity Reduced energy production Bartmann AK et al. J Assist Reprod Genet Mar;21(3):79-83 Reynier P et al Mol Hun Reprod Vol 7 No.5:

13 Past Mitochondrial Research Cytoplasmic transfer pioneered by Jacque Cohen Our research - mitochondrial enrichment from cord blood stem cells and injection into old oocytes Both result in mitochondrial heteroplasmy

14 Second Hypothesis Supplementation of mitochondrial nutrients will enhance oocyte mitochondrial energy production and improve chromosomal dysjunction

15 Mitochondrial Nutrients We tested 3 different natural vitamins that are thought to be mitochondrial nutrients: -Resveratrol -Coenzyme Q10 -Alpha-lipoic acid (ALA) Only coq10 had positive effects on oocyte mitochondrial function

16 Coenzyme Q10 Oil-soluble vitamin-like substance present in most cells, primarily in the mitochondria. Component of the electron transport chain and participates in aerobic cellular respiration to generate energy. Organs with the highest energy requirements have the highest CoQ10 concentrations.

17 Supplementation of CoQ10 Act as an antioxidant Helpful for Mitochondrial disorders Heart Failure Neurological disorders Hypertension Lifespan

18 Study Design Aged mice (n=20) 18 weeks of treatment Young mice (n=6) CoQ10 (n=10) (70mg/kg/week) Control (n=10) (vehicle)

19 Number of Oocytes Retrieved Old Mice coq10 Control

20 Nuclear Spindle Imaging Young Old plus coq10 Old

21 MMP (JC-1) 1 * * * p<0.05 Young mice Old Control CoQ10 treated 0 JC1

ROS 500000000 450000000 400000000 350000000 300000000 250000000 * p<0.01 * ** p<0.

22 ROS * p<0.01 * ** p<0.05 ** Young mice Old Control CoQ10 treated ROS

23 Mitochondrial DNA Copy Number * * ** * p<0.01 ** p<0.05 Young mice Old Control CoQ10 treated Mitochondrial DNA copy number

TREFERENCE/TARGET 1.05 1 0.95 0.9 0.85 0.8 0.

24 TREFERENCE/TARGET CONTROL YOUNG CONTROL OLD COQ10 NDUF TFAM ATP5a SDHA SOD

25 Tuba1 (Tubulin) expression

26 Number of follicles Number of follicles Number of follicles Ovarian Follicle Counts CoQ10 CoQ10 CoQ P= 0.01 P= P= 0.01 Control Control Control 0 Primordial follicles 0 Primary follicles 0 Antral follicles N = 8

27 Summary CoQ10 supplementation in old mice Improved ovarian response to stimulation Improved oocyte mitochondrial function Restored normal nuclear spindles Delayed ovarian follicle loss due to aging

28 Offspring of Older Mothers We have now performed breeding trials to determine the effect of maternal aging on the offspring Mitochondria are maternally inherited

29 Physiology

31 Fasting glucose levels P=0.002

34 Oocytes

35 P=0.001

36 Mitochondrial DNA Copy Number P=0.005

37 Lisotracker P<0.001

38 Offspring of Old Mothers Obese, insulin resistance, increased lipids (metabolic syndrome) Oocytes have mitochondrial dysfunction

39 Barker Hypothesis Exposure to an unfavorable intrauterine environment programs changes in fetal or neonatal development such that there is an increased risk of developing adult diseases Attributed to nutrient restriction in utero

40 Barker Hypothesis Maternal aging and dysfunctional oocyte mitochondria?

42 Conclusions CoQ10 supplementation appears to improve physiologic changes, ovarian response and oocyte mitochondrial function in the offspring of old mice Clinical trials now ongoing

43 Acknowledgements TCART Yaakov Bentov Navid Esfandiari Eliezer Burstein Assaf Ben Meir SLRI Andrea Jurisicova Ala Perumalsamy Collaborators Shirya Rashid (McMaster) Kelle Moley (St Louis, USA)

44 Electron Transport Chain

Rejuvenation of Gamete Cells; Past, Present and Future

Rejuvenation of Gamete Cells; Past, Present and Future Denny Sakkas PhD Scientific Director, Boston IVF Waltham, MA, USA Conflict of Interest I have no conflict of interest related to this presentation.