Insights

On Giant Tortoise Longevity

The Galapagos giant tortoises live on isolated islands in a stable environment by the equator. In a world with no predators and limited climate change, there has been less evolutionary pressure on them. Consequently evolution has favored longevity over adaptability. Contrast this with humans, where over millions years mammals have taken over from the dinosaurs, we descended from the trees into new environments, began to walk, grew larger brains, developed language and fire, and adopted new diets. The evolutionary pressure on humans has been much greater

One major contributor to adaptability are 'retrotransposons'. They are primordial viruses embedded in our genomes. Retrotransposons enable evolution by copying themselves across the genome, affecting the regulation of genes. However, this comes at a cost, as they also activate under stress and accelerate disease, in neurodegeneration, rare developmental disorders and in cancer

Transposons represent ~45% of the human genome. LINE-1 is a specific class of retrotransposon that retains the ability to copy itself (and other viral like elements) around the genome. In humans there are ~500,000 copies of LINE-1 (17% of the genome), of which 80-100 remain active. Giant tortoises historically also had active retrotransposons, but they have been completely inactivated for tens of millions of years. This is one factor enabling their exceptional longevity

LINE-1 in Cancer

The primary challenge with developing treatments for cancer is developing a target that distinguishes cancer cells from healthy cells. Tumor suppressors are often deleted or silenced, making them difficult to target directly. Oncogenes become overactived in cancer and some can be inhibited, but they are frequently also expressed in healthy tissues, limiting their therapeutic index

LINE-1 represents a different class of vulnerability. It is active in ~40% of tumors across multiple cancer types, including gastrointestinal cancers, head and neck, and lung cancer. In cancer cells it can promote pro-survival inflammatory states, tumor evolution and metastasis. Because LINE‑1 is largely silent in normal adult tissues yet reactivated in certain cancers, it represents a potentially selective and mechanistically distinct therapeutic target. The problem was, until recently, it was not practical to detect LINE-1 activity in cancer, nor was it possible to therapeutically inhibit it safely...