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Longevity Briefs: Why Do Some People ”Suddenly” Become Frail In Their 70s?

Posted on 9 June 2022

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Some people age relatively healthily for decades before seemingly experiencing a more rapid decline in their 70s and 80s, alongside a sharp increase in mortality – most people die within a fairly narrow range of ages. This is something that is relatively unique to humans, and it’s a bit of a curiosity. When scientists study what we believe to be the most important drivers of ageing at the molecular level (such as DNA damage, telomere shortening and epigenetic alterations), they have found these to build up gradually throughout life, so why do health and survival drop off abruptly? Answering that question could lead to an improved understanding of how we age and what we can do about it.

What did the researchers do: In this study, researchers collected blood stem cells (haematopoietic stem cells) from 10 human participants aged from 0 to 81 years old. Haematopoietic stem cells are the cells in the bone marrow that are capable of producing red blood cells or any of the diverse range of white blood cells. They then sequenced the genomes of these cells, with the goal of studying the genetic changes that occur throughout life.

Key takeaway(s) from this research: The stem cells accumulated on average 17 mutations per year after birth and lost around 30 base pairs (the ‘letters’ of the genetic code) per year. These numbers are similar to what has previously been measured. However, the diversity of the stem cells changed dramatically between the ages of 65 and 75.

These graphs show representations of the diversity of haematopoietic stem cells in participants above the age of 20. The graph on the left shows, for each participant along the x axis, the proportion of stem cells belonging to a clade (cells with common mutant ancestor) that represents over 1% of the stem cell population. The number of such lineages is shown above the bar, with each block within the bar representing one clade. In the 76 year-old female, for example, 12 clades account for about 45% of stem cells.
The graph on the right shows the diversity of the stem cells for each participant over age 20.

While all the cells in our body should be genetically identical (and for the most part they are), cells still acquire genetic mutations at random and pass them on when they divide, which allows us to track their ‘ancestry’. The researchers found that in people below the age of 65, a diverse population of over 20 000 stem cells contributed evenly to blood cell production. However, in people over 75, up to 60% of blood cell production had been taken over by cells from a dozen lineages or so.

Why is this a bad thing? These stem cells come to dominate over their cousins because they have acquired mutations that make them divide faster, which leads to reduced quality of the blood cells they produce and is a prerequisite for blood cancer. These cells grow in number exponentially, which may explain why frailty develops abruptly.

We’ve known for a while that the diversity of blood cells decreases with age, but this study suggests that this decline is much greater than previous estimates. A similar loss of diversity could potentially be involved in ageing in other tissues and organs throughout the body.

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    Clonal dynamics of haematopoiesis across the human lifespan:

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