Senescence and Aging

In 1961, Leonard Hayflick first observed that cultured cells ceased replicating after a finite number of divisions. Referred to as the Hayflick limit, a cell reaching this state enters into a permanent state of senescence. In addition to this hard limit, insults to the cell such as chemotherapy, hypoxia, and heat shock can also halt cellular replication and force cells into premature senescence.

While senescence plays an important role in promoting tissue repair, embryonic development, and regulating disease progression, it can also negatively impact aging.

Contemporary thought suggests that senescence provides a protective benefit in the short term but over time becomes detrimental. It is thought to be an example of antagonistic pleiotropy, a concept originally described by the evolutionary biologist George C. Williams. The concept is that natural selection can favor traits that confer a fitness advantage early in life but cause deleterious effects later in life. As an example, a cancerous cell might be forced into senescence to protect a younger organism by preventing the development of a disease state; however, the accumulation of senescent cells over the lifespan proves to be a detriment in later years.

Although senescent cells can no longer divide, they are not inert. These cells secrete chemical signals which contribute to an adverse environment, negatively affecting otherwise normal, healthy cells. This phenomenon has come to be known as the senescence-associated secretory phenotype (SASP) and is a prevalent factor of aging.

Studies have shown that the selective removal of senescent cells reduces the SASP and improves the health of an organism while extending its lifespan. Senolytic therapies have been designed to selectively remove these cells while leaving healthy cells intact. This is most often achieved by targeting specific features or pathways that are unique to these cells. Unfortunately, these therapies can be costly, moderately invasive, and often require a great deal of technical expertise.

Researchers from the University of Texas have provided preliminary evidence for a mechanical method to reduce the burden of senescent cells utilizing a low-cost, non-invasive application of low-frequency ultrasound therapy (Kumar S, et al. Rejuvenating Senescent Cells and Organisms with Only Ultrasound. bioRxiv 2022.12.08.519320).

Study Results

The authors hypothesized that brief, periodic treatment with low-frequency ultrasound (LFU) can rejuvenate senescent cells. To explore the efficacy of this therapeutic approach, the authors used cultured cells that were chemically induced into a senescent state. As is typical, these senescent cells lose their replicative capacity, exhibit an increased SASP, and undergo distinct changes to their cellular and mitochondrial structure. Cultures of these cells were treated with LFU for 20 minutes and subsequently monitored for 12-15 days.

LFU treatment ameliorated the SASP and restored replicative capacity, allowing cells to grow at a rate similar to that of non-senescent cells for the duration of the experiment. Examining individual LFU-treated cells revealed that the presence of p21, a cell cycle-regulating protein and indicator of cellular senescence, was almost entirely absent. Additionally, the normal cellular and mitochondrial structure was restored. These promising results led researchers to investigate LFU’s potential efficacy for treating the senescent cells of living animals, an important matter with regard to the potential for future clinical application.

Aged mice (22–25 months old) were treated with LFU, and a battery of tests was performed to assess both the effect on senescent cell burden and overall health.

Grip strength and treadmill running, two standard laboratory tests negatively correlated with age, were used to assess the general fitness of mice. LFU-treated mice performed significantly better in both tests when compared to control mice. The improvements seen in LSU-treated mice were similar to those seen in an additional group of mice that were subjected to exercise. Exercise itself is known to forestall age-related decline and improve cellular senescence.

To assess LFU’s effect on senescent cell populations in live animals, a second mouse experiment examined multiple molecular markers of senescence in the cells of both the kidneys and pancreas of LFU-treated animals. All molecular markers examined were significantly decreased as a result of LFU treatment, consistent with an improvement in senescent cell burden. One marker in particular, b-galactosidase, was decreased by as much as 70% when compared to untreated animals.

The ever-growing evidence implicating cellular senescence as a key driver of aging has demonstrated the importance of therapies targeting senescent cells. Previous experiments have shown the efficacy of senolytic therapies in eliminating these detrimental cells, improving both healthspan and lifespan. This study proposes a unique method to reduce the senescent cell burden through a transformative process and would likely achieve a benefit similar to senolytic therapies.

%d bloggers like this: