New study opens the door for delaying egg aging by pharmacological treatment

courtesy: Parkinsonsnewstoday.com

Recently a fascinating paper was published about a novel treatment to increase the fertility lifespan in females. The researchers have achieved a breakthrough in finding a treatment to delay the sharp decrease of fertility in females right before their mid-30s.

Research by Dr. Coleen Murphy, Professor of Molecular Biology and Genomics at Princeton University and her team reported about a protein that can preserve the fertility potential of women in mid-30s and can potentially extend eggs’ life.

The work was recently published in Current Biology, and authors were able to document an extension of eggs’ viability in two separate experiments.

Murphy and colleagues observed that a protein called cathepsin B proteases was present in abundance in aging oocytes of Caenorhabditis elegans, a nematode commonly used as an animal model for a wide variety of studies.

They also observed that many of the genes from the worm were also conserved in humans, thereby providing an important resource on understanding the aging in human’s eggs.

The researcher hypothesized that knocking of cathepsin-B genes in adult worms should result in stalling the oocyte aging and improving its quality.

They knocked down individual genes in adult worm by sing iRNA, and surprisingly the reproductive lifespan increased by 10% and morphology of oocyte also showed improvements.

Once the aging effect of cathepsin-B proteases was documented, they proceeded to treat wild-worms with a potent cell-permeable cathepsin B inhibitor (MDL-28170). This pharmacological treatment was able to slow down the decline in the quality of oocyte as the women age.

Most importantly, the drug-induced decline was achieved even when it was applied around mid-life. This has wider implications for those women who want to delay childbearing because of socio-economic commitments, they can easily gain 3 to 6 years extension in terms of fertility.

Although cathepsin B inhibitor is not yet ready for testing in humans, the research has opened new doors regarding pharmacological therapy for delaying reproductive aging. 

Abstract

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Premenopausal Bilateral Oophorectomy accelerates aging and incidence of 18 chronic morbidities.

Clinical Pearls:

• Women who had bilateral oophorectomy before menopause experienced increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. (hazard ratio, 1.22; 95% CI, 1.14-1.31; P<.001). 
• The younger the age at oophorectomy, the stronger the association with these chronic conditions.
• In these group of women, the risk of occurrence of many chronic condition was reduced by supplementing estrogen therapy.
• Study provides definitive evidence against use of bilateral oophorectomy as a means to prevent ovarian cancer in average risk premenopausal women.

Bilateral Oophorectomy is often chosen by many  as a method for prevention of ovarian cancer in premenopausal women who are at average risk of ovarian cancer. The procedure gained popularity in US when Angelina Jolie came forward about her own experiences 2 years back.She  is a carrier of mutation in BRCA1 gene putting her high risk for ovarian and breast cancer. [1]

The current guidelines from the American College of Obstetricians and Gynecologists read, "The most effective method of preventing ovarian cancer is surgical removal of the ovaries and fallopian tubes. ...The potential benefit in cancer risk reduction for premenopausal women at average risk of ovarian cancer must be balanced with the consequences of premature loss of estrogen production."

However, in practice many doctors advise patients in favor of removal of both ovaries to eliminated the risk of  getting ovarian cancer. 

Many societies around the world have formulated guidelines so that the surgery is only performed in absolutely indicated patients like BRCA1 positive patients, but the practice still continues.

Observational studies have also documented the beneficial role of estrogen in keeping chronic morbidities at bay in women who undergo bilateral oophorectomy before the age of 46 years.

The present study was prompted because of uncertainties in the risk/benefit ratio of bilateral oophorectomy for preventing ovarian cancer and the role played by estrogen in delaying many chronic morbidities which may be sign of cellular and tissue aging.

The study was published in the recent issue of Mayo Clinic Proceedings.[2]

The researchers used the Rochester Epidemiology Project records-linkage system to recruit 1653 women who underwent bilateral oophorectomy before the age of 50 years between 1988-2007 in Olmsted County, Minnesota. Each subject was than randomly matched to a control, who was also born in the same year (±1 year), but did not have bilateral oophorectomy. They were followed up for approximately 14 years to study 18 comorbidities.

At baseline it was observed that women who underwent bilateral oophorectomy were Caucasians, less educated, had increased BMI and were heavy smokers as compared to referral women. They were also more likely to suffer from mental, Cardiometabolic and somatic disorders at the time of surgery.

Researchers used inverse probability weighting to balance the baseline risk factors and individual characteristics thereby minimizing their effects as potential confounders.

Women who had bilateral oophorectomy before menopause experienced increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. (hazard ratio, 1.22; 95% CI, 1.14-1.31; P<.001). 

The younger the age at oophorectomy, the stronger the association with these chronic conditions.

In these group of women, the risk of occurrence of many chronic condition was reduced by supplementing estrogen therapy.

The researchers proposed three possible mechanisms to explain the results of the study. Although inverse probability weighting was used to rule out confounding and bring the observational study close to RCT for interpretation as possible, genetic, environmental and lifestyle factors may have acted as confounders.

Premature and abrupt decline in estrogen levels may have led to increase in ‘epigenetic age’ serving as a bio-marker for accelerated aging.

Oophorectomy leads to loss of protective effect of other ovarian hormones progesterone, testosterone, or inhibin and disrupts the hypothalamic-pituitary axis.

The study had several strengths and limitations. As all the data was extracted electronically it eliminates the recall bias and non- participation of the subjects. Study may have underestimated those conditions which do not have any medical code, as the data was extracted form records.  Statistical power was limited for some associations for the time the women were followed. It may become significant if they are followed for longer period of time.

To Conclude, the study results along with results of the earlier studies provides definitive evidence against use of bilateral oophorectomy as a means to prevent ovarian cancer in average risk premenopausal women. Study also emphasizes the protective effect estrogen may exert to delay cellular and tissue level aging which is manifested as increased risk of multiple morbidities.  

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[1]http://www.nytimes.com/2015/03/24/opinion/angelina-jolie-pitt-diary-of-a-surgery.html?_r=0

[2] http://www.mayoclinicproceedings.org/article/S0025-6196(16)30447-5/fulltext

Late Menarche, Late Menopause and Longer Reproductive lifespan linked to increased longevity.

Clinical Pearls:

• Women who had menarche at age 12 or more and experienced menopause at age 50 or beyond have increased odds of living up to age 90 as compared to women who have early menarche and early menopause.
• Those women whose reproductive life span lasted 40 years, were 13% more likely to celebrate 90 birthdays than women who were in reproductive period for 33 years. (odds ratio [OR]= 1.13).

A new study by researchers at University of California, San Diego found an interesting correlation between the age at menarche and menopause and longevity. Women who enter the reproductive period late and also have a late menopause are more likely to live till age 90.

The research implicated that women who had menarche at age 12 or more and experienced menopause at age 50 or beyond have increased odds of living up to age 90. 

According to Dr Aladdin Shadyab, of the University of California, San Diego School of Medicine "People have always wondered whether the timing of reproductive events affect longevity, but no study to date has evaluated that relationship."

The study was published in recent issue of Menopause, the journal of North American Menopause Society. [1]

The research team used data for Women’s Health Initiative study (WHI). The Women's Health Initiative (WHI) is a long-term national health study that recruited women from 1993 to 1998 and followed them until 2014 focusing on strategies for preventing chronic health diseases in postmenopausal women. This multi-million dollar, ground-breaking study has far reaching implications and have provided the health care providers with practical information to prevent and treat some of the major diseases impacting postmenopausal women. [2]

The study participants included 16,251 women from diverse racial and ethnic background all born before August, 1924. Multivariable logistic regression models were used to determine the association, adjustments were made of demographics, reproductive history and lifestyle of the women.

The average age of the study participants was 74. 7 years and 8,892 (55%) of the women lived through age 90.

As compared to those women who had an early menarche before age 12, those women who were at-least 12 or older at menarche have a 9% increased chances of living upto age 90. (odds ratio [OR]= 1.09).

Similarly, women who were at least 50 at the time of last period are 20% more likely to live till 90, as compared to women who stopped menstruating before age 50. The same was true for women who underwent surgical menopause. (odds ratio [OR]= 1.19).

Longevity was also tied to a longer reproductive life span. Those women whose reproductive life span lasted 40 years, were 13% more likely to celebrate 90 birthdays than women who were in reproductive period for 33 years. (odds ratio [OR]= 1.13).

The authors of the study cannot pinpoint a single reason behind this association, but multiple factors come into play.

Early menarche is often associated with obesity, Diabetes and CVD while early menopause is also linked to increased risk of CVD. These associated co-morbidities in women experiencing early menopause may be responsible for shorter life span.

Genome-wide association study of age at natural menopause identified genetic variants involved in DNA replication and repair pathways which is crucial in aging. Thus genetics is also an important factor.

The study has limitations of not knowing the longevity of the parents and other family members of the participants along with the work history and stress, which plays an important role in deciding longevity.

One other study published this week in Proceedings of the National Academy of Sciences and Biological Psychiatry, has shown that women with early menopause suffer from insomnia which accelerates aging and shortening the life span.[3]

The last decade has seen rapid improvement in life expectancy of older women adding average of 7 years to their life expectancy as compared to men[4] with a current total population of 1.3million women over the age of 90+.  Women surviving into their 90s outnumber men by a ratio of almost three to one.[5]

The authors conclude "With secular trends showing decreasing age at menarche, increasing age at menopause, and a concurrent rise in longevity, additional studies in younger birth cohorts will be needed in the future to precisely define the relationship between the timing of reproductive events and a woman's length of life."

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[1]http://journals.lww.com/menopausejournal/Abstract/publishahead/Ages_at_menarche_and_menopause_and_reproductive.97952.aspx

[2] https://www.whi.org/about/SitePages/About%20WHI.aspx

[3] http://newsroom.ucla.edu/releases/menopause-sleepless-nights-may-make-women-age-faster

[4] http://www.census.gov/prod/2011pubs/acs-17.pdf

[5] https://www.census.gov/newsroom/releases/archives/aging_population/cb11-194.html