A team led by the University of Rochester finds that bat fibroblasts require only two oncogenic alterations—RAS activation plus p53 or pRb inactivation—for malignant transformation. Despite this minimal barrier, bats sustain high basal p53 activity and apoptosis, alongside active telomerase, offering insights into their remarkable longevity and tumor resistance.
Key points
Bat fibroblasts from three species transform with just HRasG12V plus p53 or pRb inactivation.
All four bat species display constitutive telomerase activity in somatic cells and tissues.
Basal TP53 and WRAP53 transcripts are elevated, driving high p53‐mediated apoptosis.
Stress‐induced premature senescence triggers reduced SASP and enhanced apoptosis in bat cells.
Xenograft assays confirm two‐hit transformed bat cells form tumors in nude mice.
Genomic analyses reveal TP53 duplications in Myotis lucifugus, suggesting expanded p53 dosage.
Why it matters:
This study overturns assumptions about stringent cell‐intrinsic cancer defenses in long‐lived species by showing bats transform easily yet rely on apoptosis and immune surveillance to suppress tumors. Understanding these mechanisms could inspire novel anti‐cancer and longevity‐promoting therapies.
Q&A
What is cell‐autonomous cancer suppression?
Why do bats maintain telomerase in somatic cells?
How does p53 activation trigger apoptosis?
What are SV40 LT mutants and why were they used?
What is SASP and its significance in aging?
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Academy
Telomerase and Longevity in Mammals
Telomeres are repetitive DNA sequences (TTAGGG in vertebrates) located at the ends of chromosomes. Each time a cell divides, its telomeres shorten, eventually triggering a state called replicative senescence when excessive shortening halts cell division. While this mechanism protects against unwanted cell proliferation, it also contributes to aging and limits tissue regeneration.
Telomerase is a ribonucleoprotein enzyme that extends telomeres by adding TTAGGG repeats. It consists of a protein catalytic subunit (TERT) and an RNA template (TERC). In most human somatic cells, telomerase is repressed, preventing unlimited division and acting as a tumor suppressor. However, in certain stem cells, germ cells, and cancer cells, telomerase is active, preserving telomere length.
Telomerase Activity and Lifespan
- Somatic repression in large mammals: Large‐bodied species like humans and whales often suppress telomerase in somatic tissues to reduce cancer risk, since more cells and divisions increase mutation chances.
- Somatic activation in small mammals: Small‐bodied, long‐lived species such as bats and rodents frequently maintain telomerase activity in somatic cells, supporting tissue repair and regeneration throughout life.
Bat Longevity and Telomerase
- Exceptional lifespan: Some bat species live over 40 years despite small body size, far exceeding predictions based on metabolic rate and body mass.
- Active telomerase: Bat wing fibroblasts and multiple tissues exhibit robust telomerase activity, preventing replicative senescence in culture.
- Balanced cancer risk: Despite telomerase–mediated proliferation risks, bats offset tumor formation through enhanced DNA damage responses, elevated p53-mediated apoptosis, and likely superior immune surveillance.
Implications for Human Aging and Therapies
- Understanding how bats reconcile telomerase activity with cancer suppression may inform strategies to safely enhance tissue regeneration in humans.
- Identifying p53-mediated apoptotic pathways in bats could suggest new targets for cancer therapies that selectively eliminate damaged cells.
- Insights into bat SASP attenuation may help mitigate chronic inflammation associated with human aging and age-related diseases.
By studying mammalian telomerase regulation across species with diverse lifespans, researchers aim to decouple tissue renewal from cancer risk, paving the way for regenerative treatments and improved healthy aging.
