Genetic secrets: Why some mammals live far longer than others

Why do some mammals squeeze just a few years out of life while others live several decades?

A new cross-species study led by scientists at the University of California, Riverside (UCR), and the University of Southern California (USC) points to an answer hiding in plain sight: not just which genes are turned on, but how their messages are edited.

The team compared patterns of alternative splicing across 26 mammal species. This process trims and stitches RNA messages in mammals before cells translate them into proteins, and the species’ maximum lifespans span more than a sixteen-fold range (2.2 to 37 years).

Gene editing and mammal lifespan

What stood out most was a surprising pattern. Lifespan tracked more tightly with RNA splicing regulation than with gene expression alone.

“We’ve long known that gene expression likely contributes to lifespan controls, but our study shows that how those genes are edited through splicing offers a novel and parallel dimension to this process,” said Professor Sika Zheng.

“It’s like discovering a hidden layer of genetic control that shapes lifespan in ways we had not appreciated before.”

Professor Zheng co-led the work with Liang Chen, a professor of quantitative and computational biology at USC, together with researchers from their laboratories.

By stitching together comparative RNA datasets across mammals and tissues, the team could separate lifespan-linked splicing signals from species-specific noise.

Such an approach helps reveal what’s fundamental versus incidental in the biology of aging.

One gene, many messages

Alternative splicing lets a single gene yield multiple RNA “isoforms” by including or skipping specific segments. That flexibility multiplies the protein toolkit without adding new genes, supporting tissue specialization and rapid adaptation.

The experts profiled six tissues – including the brain – from each species, then mapped splicing events against maximum lifespan.

The picture that emerged was striking: many lifespan-associated splicing patterns are shared across distantly related mammals, and their levels scale with species longevity.

The signal held even when controlled for gene expression, underscoring splicing as an independent regulatory axis.

Mammal longevity centers in brain

Among all tissues examined, the brain lit up as a hotspot. The number of splicing events linked to lifespan in neural tissue was roughly double that seen in other organs.

Zheng argued that this feature is closely related to the brain’s unusually rich catalog of splicing factors and its need for exquisite timing and plasticity.

“This likely reflects the brain’s specialized functions and regulatory complexity, with many splicing factors expressed only in neural tissue,” said Professor Zheng.

“These findings identify the brain as a key site of lifespan regulation and suggest that longevity depends heavily on neural maintenance and adaptability. Brain-specific splicing may therefore be a promising target for promoting healthy aging and preventing neurodegenerative disease.”

Aging follows deeper rules

A key question in aging research is whether molecular changes that accompany age are causes or consequences.

Lifespan-associated splicing follows genetic programming and RNA-binding proteins (RBPs) tightly govern it – not passive aging.

“This suggests that longer-lived species may have evolved molecular programs that optimize splicing for longevity, allowing active modification of lifespan regulation in response to environmental influences,” said Zheng.

In places where lifespan-linked splicing overlapped with splicing shifts seen across age, the affected proteins often featured intrinsically flexible, disordered regions. These domains are known to boost cellular resilience under stress.

That convergence hints that splicing may tune proteomes toward stress tolerance in long-lived species and maintain that set-point as individuals age.

Can we control mammal longevity?

Much of the genomics era has focused on transcription – how much RNA a gene produces. This work argues that post-transcriptional editing deserves equal billing.

“Our study identifies splicing as a distinct, transcription-independent layer of lifespan control, revealing new molecular targets for promoting resilience and healthy aging,” said Zheng.

The implication is practical as well as conceptual. Researchers could one day steer interventions that modulate RBP networks or splice-site choice – approaches already used in approved RNA-targeted therapies – toward preserving brain function and systemic healthspan in mammals.

From mechanism to medicine

The study doesn’t claim that splicing alone dictates lifespan. Diet, environment, damage repair, and many other pathways matter.

But by showing that conserved splicing programs scale with species longevity, it provides a roadmap for where and how to look next.

It also reframes longevity as something organisms actively configure. They do not merely endure it, but instead shape it through regulatory choices layered on top of the static genome.

Future research on mammal aging

The next steps are already clear. First, scientists will identify the specific RBPs that anchor these longevity programs. Then they will test whether tweaking those RBPs in model systems preserves neural adaptability and stress resistance.

Next, they will explore how environmental inputs (diet, sleep, temperature, social factors) nudge the splicing landscape toward healthier trajectories.

If splicing is part of the body’s built-in playbook for a longer, more resilient life, we may finally gain a deeper understanding of the process of aging.

The study is published in the journal Nature Communications.

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