Unveiling the mysteries of senescent cells and their effect on aging

Researchers are bridging mouse and human data to reveal the biology of senescent cells.

Multiple researchers at the Jackson Laboratory (JAX) are taking part in an ambitious research programme spanning several top research institutions to study senescent cells.

Longevity.Technology: Senescent cells – often called zombie cells – stop dividing in response to stressors but don’t die. Instead, they linger on in biological limbo, producing a complex toxic secretome cocktail called SASP, and causing age-related tissue and organ dysfunction and various chronic age-related diseases. These stressors can be a variety of environmental and internal damaging events, including abnormal cellular growth, oxidative stress and autophagy factors.

Studies show that senescent cells have a role to play in both human health and the aging process, and recent research with mice suggests that the clearing of senescent cells delays the onset of age-related dysfunction and disease as well as all-cause mortality.

Could therapies that remove senescent cells – called senotherapeutics – also improve the health of humans as we age?

Promising clinical trials of senotherapeutics are already underway, but there is still much to be understood about where and when senescent cells arise in our bodies, how they differ from cell to cell and tissue to tissue and how can they be reliably differentiated from the non-senescent cells that vastly outnumber them? Finding the answers to these questions could significantly advance human healthspan and lifespan, and the National Institutes of Health (NIH) has launched an extensive research initiative for this very purpose.

READ MORE: Making sense of senolytics and tackling senescence

The SenNet Consortium, a collaboration of institutions from throughout the US, was initially launched in 2021 with centres established to gather and analyse human data. The researchers will collect and analyse 18 tissues from healthy humans across the lifespan to discern the full scope of senescent cells and how they may contribute to the aging process. The work of the SenNet Consortium was recently presented in a paper published in Nature Aging [1].

JAX Professor Paul Robson, PhD
JAX Professor Paul Robson, PhD // Photograph: JAX

Along with colleagues from Mayo Clinic, University of Texas Health Science centre at San Antonio, and UConn Health, JAX Professor Paul Robson, PhD is taking part in the mapping of four human tissue types (kidney, adipose, pancreas and placenta) within the KAPP-Sen Tissue Mapping Center.

SenNet has also grown over the past year to add mouse-focused investigators, and JAX was designated as a Tissue Mapping Center (TMC) for SenNet in August 2022, supported by a four-year, $10.7 million grant from the National Institute on Aging.

JAX is poised to make substantial contributions to SenNet by profiling senescent cells in kidney, placenta, pancreas and heart – all tissues that are relevant to chronic diseases of aging. The team will draw upon its genetically diverse mouse resources, including Diversity Outbred mouse populations, to model a range of molecular senescence traits, as well as inbred mice specifically engineered to help visualise senescent cell subsets.

As three of the tissues (kidney, pancreas and placenta) in the mouse JAX-Sen TMC are shared with the human KAPP-Sen TMC, these efforts align well with the JAX institutional initiative to continue to build the human-mouse interface. The goal of SenNet goes beyond building an atlas of senescent cells in the body and knowing more about senescent cell biology. The potential benefits of senotherapeutics for healthy human aging are exciting, as are other possible clinical advances, such as identifying individuals at higher risk for age-related disease.

“JAX, with our outstanding Scientific Services, mouse resources, and access to human tissues through our collaborators, is in an ideal position to make inroads into the understanding of senescent cells,” says Robson. “Better knowledge of this important biological phenomenon should have an impact on healthy aging and cancer prevention [2].”

[1] https://www.nature.com/articles/s43587-022-00326-5
[2] https://www.jax.org/news-and-insights/2022/December/cellular-senescence-and-healthy-aging