This photograph shows two fast-aging mice. The mouse on the left was treated with a FOXO4 peptide, which targets senescent cells and leads to hair regrowth in 10 days. The mouse on the right was not treated with the peptide. [Peter L.J. de Keizer]
This photograph shows two fast-aging mice. The mouse on the left was treated with a FOXO4 peptide, which targets senescent cells and leads to hair regrowth in 10 days. The mouse on the right was not treated with the peptide. [Peter L.J. de Keizer]

Relieved of the burden of senescent cells, we may enjoy extended healthspans—or even lifespans. This notion was put the to the test by a team of scientists based at Erasmus University Medical Center. They selectively eliminated senescent cells in aging mice, which responded by showing a reversal of age-related loss of fur, poor kidney function, and frailty.

When cells become damaged, they resort to senescence—cell cycle arrest—to avoid contributing to the proliferation of flawed cells, which can give rise to diseases such as cancer. Yet senescent cells remain metabolically active, and they secrete factors that promote inflammation. In fact, the senescence-associated secretory phenotype contributes to type 2 diabetes, atherosclerosis, and other age-related diseases.

These conditions become increasingly likely as senescent cells accumulate over time. To delay the onset of such conditions, and the debilities of aging generally, scientists have been exploring various ways to prevent or at least slow the accumulation of senescent cells. A new way has been demonstrated by the Erasmus scientists. They have shown that regular infusions of a peptide that can selectively seek out and destroy senescent cells can improve healthspan in naturally aged mice and mice genetically engineered to rapidly age.

Details of this work appeared March 23 in the journal Cell, in an article entitled “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.” The article describes the development of a peptide that can interfere with apoptotic signaling in senescent cells without perturbing normal cells. This peptide can restore tissue homeostasis, even after loss of health has already occurred.

“Here, we identify FOXO4 as a pivot in senescent cell viability,” wrote the article’s authors. “We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis.”

Essentially, the peptide blocks the ability of a protein implicated in senescence, FOXO4, to tell another protein, p53, not to cause the cell to self-destruct. By interfering with the FOXO4–p53 crosstalk, the peptide causes senescent cells to go through apoptosis, or cell suicide.

“Only in senescent cells does this peptide cause cell death,” says senior author Peter de Keizer, Ph.D., a researcher of aging at Erasmus University Medical Center in The Netherlands. “We treated mice for over 10 months, giving them infusions of the peptide three times a week, and we didn't see any obvious side effects. FOXO4 is barely expressed in nonsenescent cells, so that makes the peptide interesting as the FOXO4–p53 interaction is especially relevant to senescent cells, but not normal cells.”

Results appeared at different times over the course of treatment. Fast-aging mice with patches of missing fur began to recover their coats after 10 days. After about 3 weeks, fitness benefits began to show, with older mice running double the distance of their counterparts who did not receive the peptide. A month after treatment, aged mice showed an increase in markers indicating healthy kidney function.

“Under conditions where it was well tolerated in vivo,” the article’s authors added, “this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity.”

Senescent cell therapy is one of several strategies being tested in mice aimed at reversing aging or lengthening healthspan. In 2015, the Valter Longo, Ph.D., laboratory at the University of Southern California Leonard Davis School of Gerontology reported that mice on a calorie-restricted diet that mimics fasting benefited from a longer life, a reduction in inflammatory disease, and improved memory. And last December, Juan Carlos Izpisua Belmontem, Ph.D., at the Salk Institute for Biological Studies and colleagues made headlines with their discovery that cellular reprogramming of epigenetic marks could extend lifespan and improve health in fast-aging mice.

“This wave of research on how we can fight aging is complementary, and not in competition,” said de Keizer. “The common thread I see for the future of antiaging research is that there are three fronts in which we can improve: The prevention of cellular damage and senescence, safe therapeutic removal of senescent cells, and to stimulate stem cells—no matter the strategy—to improve tissue regeneration once senescence is removed.”

de Keizer aims to start a company based on these findings, but in the short term, he and his group want to show that their peptide is nontoxic in humans with no unforeseen side effects. They plan to offer a safety clinical trial in people with glioblastoma multiforme, an aggressive brain tumor, which also shows high levels of the biomarkers needed for this FOXO4 peptide to be effective.

The FOXO4 peptide is currently being tested for whether it can also extend lifespan. Human safety studies are being planned.








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