Longevity Briefs: What Are The Most Important Organs For Longevity?

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.

The problem:

Different organs do not appear to age in the same way or at the same rate, which complicates both the measurement of biological ageing and the search for ways to slow it down. Scientists can estimate how rapidly someone is ageing by looking at epigenetic modifications – changes to the DNA molecule that do not alter the genetic code itself, but how it is read. Epigenetic changes are usually measured in white blood cells collected from a blood sample, but this doesn’t tell us about the age of individual organs like the heart or the brain, which requires the collection of the relevant cell type.

Another approach is to study the levels of proteins in the blood that correlate with ageing in different organs. Protein levels change with age as a consequence of more fundamental components of the ageing process. Building a solid model of how these levels correspond to ageing in different organs could allow us to estimate biological age more comprehensively and improve our understanding of how ageing in different organs impacts future health and lifespan.

The discovery:

In this study, researchers aimed to determine whether proteins in the blood could serve as reliable indicators of biological age and predict future health outcomes. They first analysed protein data from 44,498 individuals aged 40 to 70 sourced from the UK Biobank, a large-scale health resource that collects genetic and health information from participants. Focusing on 2,916 proteins, they developed machine learning models to estimate the biological age of 11 major organs based on the levels of organ-specific proteins. They then looked at the difference between estimated organ age and each participant’s actual (chronological) age as an indicator of whether the organ was ageing faster than expected.

Looking at 17 years of followup data, the researchers found that these organ ‘age gaps’ were associated with significantly increased risk of age-related disease in the relevant organ. A faster ageing heart was associated with increased risk of heart disease; faster ageing kidneys were associated with increased risk of chronic kidney disease and so on. However, the most impressive associations were for the rate of brain ageing.

Those with the fastest-ageing brains (specifically the top 6-7%) were 3.1 more likely to develop Alzheimer’s disease than those with normally ageing brains, while the slowest-ageing brains reduced risk to about a quarter. This was independent of any genetic risk factors – if a participant’s proteins indicated they had a rapidly ageing brain, they were more at risk than someone with the same genetic predisposition. To put this risk into perspective, a protein profile linked to accelerated ageing was associated with an increase in Alzheimer’s risk similar to that conferred by a single copy of ApoE4, a gene variant strongly associated with Alzheimer’s.

The researchers also found that having a higher number of rapidly ageing organs was associated with progressively higher mortality risk during the followup period, but only a slowly ageing brain or immune system was associated with reduced mortality risk. Finally, the researchers analysed the relationship between lifestyle factors and rate of organ ageing. They found that factors such as smoking, alcohol and processed meat intake and insomnia were associated with more rapid ageing, while exercise, healthy food intake and education were associated with slower ageing. They also found that women who experienced menopause earlier in life had more rapidly ageing organs on average, while those taking hormone replacement therapy had more youthful organs.

The implications:

Measuring protein levels in the blood could be an effective way to estimate the rate of ageing in multiple organs at once. Since this rate of ageing correlates with age-related diseases, there’s also an opportunity to intervene based on these measurements. It’s not clear to what extent changes in these proteins drives ageing, as opposed to protein disturbances being a consequence of accelerated organ ageing prior to the development of any age-related disease. However, given their correlation with lifestyle factors known to modify the risk of age-related diseases, it seems very likely that knowledge about these protein levels would be actionable regardless.

This research also suggests that the rate of brain and immune system ageing might be particularly important for lifespan. It implies that interventions that slow ageing in these systems specifically could be especially valuable. This makes sense given that both these organ systems are responsible for controlling and overseeing processes related to ageing, such as the brain’s control of sleep cycles or the removal of senescent cells by the immune system.