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A Genetic Switch Could Be Key to a Long and Healthy Life

A single amino acid change in a tumour suppressor protein extends health while maintaining longevity in roundworms.

According to the World Health Organization, 1 in every 6 people or around 1.4 billion people worldwide will be aged at least 60 years by 2030. By 2050, this number will nearly double to 2.1 billion. While the increasing proportion of older people and length of life may be considered a human success story and a reason to celebrate medical advancements, population ageing has brought a new set of challenges. With older age, we are more likely to develop chronic illnesses and age-related diseases including but not limited to dementia, diabetes, heart, and pulmonary diseases simultaneously. Ageing is also characterised by the emergence of geriatric syndromes such as frailty, pressure ulcers, and urinary incontinence. Given these concerns, healthy ageing has become an important pillar of research to ensure that the additional years of life can be spent more meaningfully.

Recently, researchers at the Korea Advanced Institute of Science and Technology have uncovered important insights into how health span can be improved by regulating the activity of a special protein. Led by Professor Seung-Jae V. Lee from the Department of Biological Sciences, the team has discovered that a single amino acid change in the protein phosphatase and tension homolog (PTEN), a well-conserved tumour suppressor protein, can significantly prolong healthy periods while maintaining longevity. Their findings suggest that PTEN-targeted therapeutics may help promote healthy longevity.

In various species ranging from humans to roundworms, the insulin and insulin-like growth factor-1 (IGF-1) signalling (IIS) pathways regulate a number of physiological aspects. Notably, it is one of the most evolutionarily conserved ageing-related pathways and plays a crucial role in longevity. According to some studies, a genetic mutation in the insulin/IGF-1 receptor gene that causes a reduction in IIS successfully increased lifespan in model organism C. elegans. However, a decrease in IIS generally compromises health on several levels and impedes growth, motility, and reproduction.

To uncouple the link between longevity and poor health, Prof. Lee and colleagues examined how genetic changes in particular parts of the IIS could affect health and lifespan in C. elegans. The team studied daf-18, which encodes a worm ortholog of PTEN phosphatase. Through a large-scale mutagenesis screen, they discovered that a specific daf-18 mutation that changes a cysteine to tyrosine in the PTEN protein successfully improved health while retaining IIS reduction-induced longevity.

In particular, the single amino acid change maintained the long lifespan, enhanced immunity, and improved the reduced motility of mutated adult C. elegans. It was also reported to cause a delicate recalibration of IIS activity – protein phosphatase activity was maintained while lipid phosphatase activity was reduced. Moreover, this mutation partially maintained the activity of the longevity-promoting transcription factor Forkhead Box O (FOXO) protein but prevented the upregulation of the NRF2 transcription factor. The combination of these effects supported healthy longevity in animals with reduced IIS.

Having presented valuable insights into how PTEN can coordinate animal health and longevity, the team is excited about the implications of their findings for developing therapeutics and potential strategies to safely promote healthy ageing.

“Our study raises the exciting possibility of simultaneously promoting longevity and health in humans by slightly tweaking the activity of one protein, PTEN,” said Prof. Lee. [APBN]

Source: Park et al. (2021). A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling. Nature Communications, 12, 5631.