Photo courtesy Rod Long, Unsplash
The last few decades have seen a dramatic leap in life expectancies across developed countries—people are living longer than ever before, and the age of the centenarian could soon be upon us.
For example, in the ‘70s Canadians lived an average of 72.7 years. Today, that number has risen by around a decade. Looking ahead, could advances in biogerontology help push the limits of longevity even further?
Most likely, says a growing body of research. The key to unlocking longer, healthier lives are specific genes that exert strong controls on lifelong health and patterns of aging. Before we can develop gene therapies to modulate the activities of these “aging” genes, we first have to identify them.
Scientists report finding one of these needles in the genomic haystack in a breakthrough study published earlier this year. Researchers screened a panel of around 10,000 genes in search of potent influencers of cellular senescence, a hallmark of aging where cells enter a state of permanent growth arrest. To do this, the team performed a genome-wide screen using a CRISPR-based platform, mining for genes in human mesenchymal precursor cells isolated from embryonic tissues bearing mutations associated with rare, hereditary accelerated aging disorders.
Of the thousands of screened genes, around one percent were found to impact cellular senescence. Among these, however, was a single standout: a gene called KAT7.
KAT7 belongs to a diverse group of enzymes known as histone acetyltransferases, cellular components that are evolutionarily conserved from yeasts to humans. These proteins are known to play central roles in chromatin remodeling and act as transcriptional regulators to control gene expression. The researchers found that switching off KAT7 triggered a cascade of molecular events resulting in cells staying younger for longer.
Taking a deeper dive into this exciting finding, the team developed an experimental gene therapy that used a lentiviral vector to deliver a CRISPR-based therapeutic. The gene editor was designed to inactivate KAT7 in vivo, working specifically in liver cells. The researchers administered the treatment intravenously to both normal aged mice and a cohort of genetically modified animals that act as a model of accelerated aging.
The results were striking. After around half a year, the treated mice showed a reduction in aging markers, more grip strength, and lived 25 percent longer than the untreated controls.
Promisingly, no toxicity or observable side effects were noted in the animals that received the KAT7 gene therapy. Still, many other questions need to be answered before the KAT7 gene therapy is ready for clinical prime time.
Among these is the unknown of whether extinguishing KAT7 activity may prompt unwanted knock-on effects in other critical genes. This risk is particularly concerning given the history of CRISPR therapeutics mistakenly editing off-target genes.
Besides these mechanistic hurdles, innovative new anti-aging gene therapies also come with ethical and philosophical considerations. Often, living longer doesn’t guarantee living better. A combination of health-enhancing treatments will likely need to be administered to tackle accompanying age-related pathologies such as osteoporosis, cancer, neurodegenerative diseases, and cardio-metabolic conditions. Moreover, because the genetic and environmental contributors to aging are so complex and interconnected, it’s unlikely that a single gene therapy will be a panacea for aging.
My blog is just one of many covering the topic of aging as part of Signal’s sixth annual blog carnival. Please click here to read what other bloggers think about this.
Tara Fernandez
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