Navitoclax May Speed Wound Healing in Aged Skin Before Surgery

Wound care is inherently reactive. Once a cut occurs, the body’s response begins with clotting, inflammation and the formation of new tissue.

Treating skin before an injury has occurred has, until now, remained a theoretical concept. A new study tested that premise by applying a drug to aged skin before creating a wound.

The treatment seemed to accelerate healing through an entirely unexpected mechanism.

Skin’s persistent residents

As skin grows older, some cells stop dividing yet do not die. Instead, they stay within the tissue and release inflammatory signals. Researchers refer to these as zombie cells, or, more formally, senescent cells.

In older human skin, such cells may account for around 15% of the outer and middle layers. Their accumulation has been associated with thinner skin, poorer structural strength and slower wound healing.

The research team was led by Dr Daniel S. Roh, a reconstructive surgeon at Boston University Aram V. Chobanian and Avedisian School of Medicine (BUMC).

Their aim was to remove these cells from older skin and observe the effects.

The topical navitoclax experiment

The researchers selected navitoclax, a drug in the class known as senolytics.

This type of medicine removes ageing cells by blocking the proteins that allow them to survive longer than they should.

Senescent cells depend on these survival proteins. At a low dose, the drug encourages them to destroy themselves while largely sparing healthy cells.

Previous human trials used oral forms of the drug and encountered side effects, including reduced platelet counts. The Boston team took another approach.

They applied a low concentration of the drug to the backs of 24-month-old mice for five days beneath a clear dressing. These animals were comparable with people in their seventies.

Faster wound closure

Once the five-day treatment ended, the team created a small wound on each mouse and photographed the site every three days. Skin receiving the treatment closed at a clearly quicker rate.

By day 18, one-third of treated mice had completely closed wounds, while no untreated mice had done so. At day 24, 80% of the treated group had healed, compared with 56% of the controls.

Before any wounds were made, treated skin also differed at the cellular level.

Tissue samples contained fewer signs of cellular ageing, including the proteins and enzymes normally used by researchers to identify senescent cells in laboratory samples.

Inflammation that helped

One result surprised the researchers. Immediately after the five-day course, the skin showed inflammation.

Greater numbers of immune cells had entered the tissue, while macrophages - immune cells that help remove debris - had accumulated in both skin layers.

Although inflammation generally indicates a problem, that did not appear to be the case here. The short-lived immune response seemed to prime the tissue for injury.

After a wound was created, the skin sealed more quickly than untreated old skin, with its repair mechanisms already prepared.

When senescent cells die, they are likely to release internal material that serves as an alarm signal. Macrophages respond and remain poised for an injury.

A short, regulated burst of inflammation may simply be the price of removing aged cellular debris.

Changes beneath the surface

To examine molecular changes, the team assessed gene activity in treated and untreated skin.

Hundreds of genes were altered. The pattern indicated that this was linked to programmed cell death, the mechanism through which the drug removes its targets.

More notably, wound-healing pathways had activated despite the absence of a wound.

Genes involved in blood clotting, the formation of new blood vessels, cell division and collagen production all displayed increased activity in treated skin.

Ageing skin loses a substantial amount of collagen, while the collagen left behind becomes fragmented - a well-established feature of skin ageing.

At least at gene level, the treatment shifted cells towards more youthful production.

Keeping the treatment local

The broader use of senolytics has raised another concern. These drugs have not entered routine medical use, partly because of their side effects.

Earlier oral treatments reduced platelet levels and altered immune cells, making extended treatment more difficult. The topical approach avoided both issues.

Blood tests from treated mice found normal platelet levels and slightly raised neutrophils.

The drug appeared to remain at the application site rather than circulating through the bloodstream to any meaningful extent.

The researchers also identified what the drug did not achieve. Young mice, aged only two months, received the same treatment but showed no reduction in senescence markers.

The drug appears to work mainly where large numbers of its targets are present, rather than where they occur only in isolated instances.

Clearing ageing cells before surgery

The clearest immediate use may be pre-operative care for older patients. Elective and reconstructive procedures in elderly people are often complicated by delayed healing, wound separation and infection.

A short treatment applied to the skin before an incision could alter those chances.

Before this study, no research had shown that a topical senolytic could hasten healing in aged mammals while avoiding the systemic drawbacks of oral dosing.

The findings point to a new method of preparing aged tissue for repair. Different senolytics may be better suited to particular age groups or wound types, and human trials are expected to follow.

For the moment, experimental evidence supports clearing ageing cells before surgery, potentially giving elderly patients one fewer reason to worry about a prolonged recovery.