Science advancesAug 26, 2026

Creating pigs with increased mitochondrial DNA mutations and early aging using precise gene editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 30, 2026

Abstract

Pigs with a proofreading-deficient POLG showed increased mtDNA mutations and signs of premature aging.

The deficiency in proofreading function of POLG led to elevated levels of somatic mtDNA mutations in the pigs.
Key premature aging characteristics observed included weight loss, rough hair coat, and anemia.
Structural changes were noted in the skin and testicular tissue of the pigs.
Increased cell death (apoptosis) and higher levels of markers associated with aging were recorded.
These pigs exhibited a shortened life span, suggesting links between mtDNA mutations and aging.

Simplified

The accumulation of mitochondrial DNA (mtDNA) mutations is a primary driver of mitochondrial dysfunction, which is intrinsically linked to aging and various pathologies. POLG, the catalytic subunit of DNA polymerase gamma, is essential for mtDNA replication; notably, a deficiency in its proofreading function precipitates the accumulation of mtDNA mutations. In this study, by combining prime editing with somatic cell nuclear transfer technology, we successfully generated a mitochondrial mutator pig model expressing proofreading-deficient POLG. These pigs exhibited elevated somatic mtDNA mutation loads and recapitulated key premature aging phenotypes, including weight loss, rough hair coat, anemia, structural alterations in the skin and testicular interstitium, increased apoptosis, and the up-regulation of senescence-associated markers, culminating in shortened life span. Given the physiological and metabolic similarities between pigs and humans, this mitochondrial mutator pig model represents an ideal preclinical tool for dissecting the mechanistic role of mtDNA mutations in aging and age-related pathologies and for accelerating the translation of therapeutic strategies.

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Creating pigs with increased mitochondrial DNA mutations and early aging using precise gene editing

Abstract

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