The pace of biological aging in women is doubling during perimenopause and IgG glycans may predict it.

Longevity.Technology: Newson Health Research Education and GlycanAge are conducting a joint “GlycanAge menopause study” to understand how low hormones levels during, and after, the menopause impacts antibody glycosylation. Antibodies are important effectors of the immune system and they actively suppress overactivation of inflammation in young women. However, with aging, particularly during transition to menopause, “young” glycans on antibodies decline and are exchanged with “old” glycans that promote inflammation.

Perimenopause can be a period of turbulent hormonal changes that precede the menopause which is when periods stop. It is often accompanied by symptoms such as hot flushes, fatigue, low mood, reduced motivation and anxiety. Further, the perimenopause and menopause increases the risk of developing numerous diseases such as osteoporosis, dementia, cardiovascular disease and even cancer. For most women, menopause occurs between 45 and 55 years of age, but perimenopause can affect even women in their 20s and 30s. Early detection of the perimenopause is important for timely treatment, intervention and prevention of both symptoms and diseases associated with perimenopause.

What happens during perimenopause?

“During the perimenopause hormones levels including oestradiol start to fall and then they are very low in menopause. We have known for decades that menopausal women have an increase of diseases such as heart disease, osteoporosis, diabetes, clinical depression and dementia. Other research has shown that the link to all these diseases is the harmful, low grade inflammation that occurs which can be triggered by low oestradiol levels,” says Dr Louise Newson, GP and menopause specialist at Newson Health.

Glycosylation, the attachment of sugar moieties to proteins, is an important and highly regulated mechanism essential for almost every process in the living world. Studies of rare genetic disorders that affect glycosylation first highlighted the biological importance of the glycome. It is now known that changes in glycosylation can regulate inflammatory responses, aid viral immune escape, regulate apoptosis and promote cancer cell metastasis.

In humans, glycosylation of immunoglobulin G is an important regulator of immunity. Large population studies discovered that every individual has a unique mixture of glycans on Immunoglobulin G, collectively called the IgG glycosylation profile. The aging process is associated with the transition of an individual’s IgG glycan profile from “young” and anti-inflammatory to “old” and pro-inflammatory.

In females, this change is particularly pronounced in the time preceding the average age of menopause. This observation led to the theory that oestrogen may be regulating IgG glycosylation, which may explain why the IgG glycome in premenopausal women reflects an apparent lower biological age.

Developing a test for perimenopause

Using glycoprofiling technology, a recent randomised placebo-controlled clinical study, conducted at the University of Colorado Anschutz Medical Campus, demonstrated that deprivation of gonadal hormones resulted in a median increase of glycan age of 9.1 years. Moreover, treatment with transdermal oestradiol therapy completely prevented the increase in biological age. This result suggested that oestradiol could be a factor that defines the glycan age of an individual [1].

“After analysing the IgG N-glycome in over 100,000 people we developed the GlycanAge test of biological age that is helping people to manage their health better. Recently our focus has shifted to perimenopause, since our initial data suggested that women experience increased pace of biological ageing in this period. In this current large study, on a unique cohort of twins, performed in a collaboration with Professor Tim Spector and his team, we managed to confirm this observation,” says Gordon Lauc, Chief Scientific Officer of GlycanAge.

To validate these findings, the association of IgG glycome changes with perimenopause was explored by analysing IgG N-Glycome composition in 5,080 samples from 1,940 females at multiple time points during their transition from pre-menopause to menopause. The study, conducted in collaboration with the Department of Twin Research & Genetic Epidemiology of the Kings College London, is still undergoing independent peer review, but the performed analysis shows that the pace of aging of the immune system significantly increases during perimenopause which is when oestradiol levels start to decline in women. First results of this study have just been released in a form of a preprint posted on the MedRxiv repository [2].

Linking health and perimenopause

This could be an important observation since the “old” IgG glycome is associated with future development of numerous diseases, suggesting that the changes in IgG glycosylation may be a molecular link between menopause and increased health risks that are associated with menopause. GlycanAge believes that IgG glycans may prove to be an ideal marker for determining the perimenopause.

“The pace of biological aging during perimenopause was more than double of the normal pace and we are looking forward to more research in collaboration with Newson Health to see whether this can be prevented by hormone replacement therapy,” says Gordon Lauc.
[1] https://pubmed.ncbi.nlm.nih.gov/33049709/
[2] https://www.medrxiv.org/content/10.1101/2021.04.10.21255252v1