Genetic and Lifestyle Factors in Human Longevity: Insights from a Landmark Study

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• Dutch Longevity Study Design
• Key Findings on Health Markers
• Genetic Analysis and Longevity
• mTOR Pathway and Aging
• Clinical Implications of Genetic Research
• Full Transcript

Dutch Longevity Study Design

Dr. Andrea Maier, MD, describes the unique setup of the Leiden Longevity Study. Researchers recruited nonagenarians, individuals in their nineties, who had a sibling also in their nineties. This sibling pair design indicated a strong familial propensity for long life. The study also included the offspring of these nonagenarian siblings, who share 50% of their genetic makeup. As a crucial control group, the partners (spouses) of the siblings were included. Dr. Andrea Maier, MD, explains this allowed scientists to compare the influence of genetics versus shared environment and lifestyle.

Key Findings on Health Markers

The research revealed significant physiological differences in the offspring of long-lived individuals. Compared to their partners, these offspring exhibited much lower glucose levels and a superior glucose regulatory system. Dr. Andrea Maier, MD, notes that lower glucose is associated with a reduced risk of developing diabetes. Other hormones, like thyroid hormone, were also differentially regulated in the long-lived families. Importantly, by age 60, the offspring already showed a lower prevalence of age-related diseases than their partners. These findings provided concrete evidence that longevity and healthspan traits run in families.

Genetic Analysis and Longevity

Dr. Anton Titov, MD, and Dr. Andrea Maier, MD, discuss the genetic component of aging. Scientific consensus estimates that genetics account for about 20% of a person's longevity. The study, led by Principal Investigator Dr. Eline Slagboom, aimed to identify specific genes linked to long life. While a single "longevity gene" was not discovered, the analysis identified genes associated with disease that were absent in long-living families. The ApoE gene, known for its association with dementia risk, was one gene linked to longevity outcomes. Dr. Andrea Maier, MD, emphasizes that longevity is influenced by a complex network of genes, not just one.

mTOR Pathway and Aging

A critical discovery involved the mTOR signaling pathway. Genes within this pathway were found to be differentially expressed in the long-lived families. Dr. Andrea Maier, MD, explains that the mTOR pathway is fundamental to cellular function. It plays a central role in protein synthesis and various cellular signals. Dysregulation of mTOR is strongly associated with the development of disease and the aging process itself. This finding points to a key biological mechanism that may be optimized in individuals predisposed to a longer, healthier life.

Clinical Implications of Genetic Research

Dr. Anton Titov, MD, explores the potential for clinical application of this research. Dr. Maier is clear that genetic analysis for predicting longevity is not yet ready for use in patient care. While certain genes are known to increase the risk for diseases like cancer or cardiovascular disease, the network for longevity is more complex. The goal of this research is to better understand the biology of aging itself. Similar study designs in Italy with centenarians have corroborated these findings. Dr. Andrea Maier, MD, concludes that this work builds a foundation for future interventions to promote healthy aging in the broader population.

Full Transcript

Dr. Anton Titov, MD: Human longevity is affected by both genetics and lifestyle. You studied blood samples from a cohort of Dutch families who showed increased longevity, living a very long time across several generations. What have you learned from your genetic analysis of aging in this Dutch families' longevity study?

Dr. Andrea Maier, MD: I was fortunate while I was in Leiden, doing my internal medicine studies, to work with the Leiden longevity study and the Leiden 85-plus study. The Leiden longevity study is a very nice setup. We recruited nonagenarians and their nonagenarian siblings.

It means that somebody who has at the age of 90 a brother or sister also being 90. It shows the propensity that there's something special in these families, because you have two siblings in the family with long life. We also included the offspring, because 90-year-olds are quite fragile. I wouldn't say that they are frail, but it's very important for us to see how their offspring are doing.

The offspring, of course, have 50% of the genetic makeup of these nonagenarian siblings. The principal investigator of the study is Dr. Eline Slagboom from Leiden. We also included the partners of the siblings as a control for the offspring of the nonagenarian siblings.

We wanted to see what is the influence of living a long life in the family and having the controls next to that. So the controls are the husbands and the wives of these nonagenarian siblings.

What we were able to find is that yes, it seems that longevity runs in families. The offspring of the nonagenarian siblings, for example, was compared to their husbands and wives living together with them. Nonagenarians had a much lower glucose level, and they had a better glucose regulatory system.

We know that if the glucose level is a little bit lower, you have less chance of having diabetes, etc. But also other hormones like thyroid hormone were differentially regulated. We were already at the age of offspring of nonagenarians, at about 60 years.

We were able to see that they have less age-related diseases compared to their partners. It already then says, yes, it's proven that something is running in the families. These individuals were included in the genetic analysis because it might be the genes are very important for longevity.

Longevity scientists think that about 20% of longevity is based on genetic makeup. We were able to find some genes like the ApoE gene was associated with longevity. But we really couldn't find a longevity gene. But we could find genes associated with diseases, which were absent in the individuals out of the long-living families.

Very nice! We were also able to show that some genes were more highly expressed than others. So one of the gene families is in the mTOR pathway, for example. We saw that in the long-living families, these genes were differentially regulated.

And mTOR is very important for making proteins and for lots of cellular signals. The mTOR pathway is associated with the occurrence of disease and aging. So while having this very nice study design, we were able to dig a little deeper into the biology and show that offspring of nonagenarian siblings are quite different compared to their partners.

And luckily, there have been study designs also doing that, for example, in Italy. It included centenarians and the offspring. And there are many other cohort studies now. They also show the same results to get a better understanding of the aging process itself.

So, for example, it's the ApoE gene and certain alleles associated with the onset of dementia. So there is a huge network of genes. And that's not only one gene or the other gene, but it's a gene network, which is associated with longevity.

So if you asked me this: is the genetic analysis ready to be implemented into clinical care? Can we say, okay, you have a good genetic makeup or not? Also here, as I said for other biomarkers of biological age, that's not ready yet for introduction into clinical care.

But what we know is there are certain genes which are more associated with the development of cancer or cardiovascular disease. But of course, these are genes being associated with the disease. Whereas we were looking for genes associated with longevity.