Removing Senescent Cells from the Lungs of Old Mice Improves Pulmonary Function and Reduces Age-Related Loss of Tissue Elasticity

The open access paper linked below provides another reason to be optimistic about the therapies to clear senescent cells from old tissues that are presently under development. Here, the researchers created genetically engineered mice in which they could selectively trigger senescent cell death in lung tissues. In older mice, the result was improved pulmonary function, and other improvements in the state of lung tissue - turning back the clock on some of the detrimental age-related changes that take place in the lungs.

Cells become senescent in response to damage or environmental toxicity, or at the end of their replicative lifespan, or to assist in wound healing. The vast majority either destroy themselves or are destroyed by the immune system, but a few manage to linger on. Those few grow in numbers over the years, and more so once the immune system begins to decline and falter in its duties. Ever more senescent cells accumulate in tissues with advancing age, and they secrete a mix of signals that can encourage other cells to become senescent, increase inflammation, and destructively remodel nearby tissue structures. In small numbers senescent cells can help to resist cancer or assist healing, but in large numbers they contribute meaningfully to all of the symptoms and conditions of old age. They are one of the root causes of aging.

Building therapies to destroy senescent cells is the best, easiest, and most direct response. If carried out sufficiently well it would remove this contribution to the aging process entirely, and fortunately the cancer research community has been working on targeted cell destruction for many years now: the technologies exist and just need to be hammered into shape. This class of rejuvenation therapy has been advocated as a part of the SENS vision for the medical control of aging for going on fifteen years now, but only in recent years has the research community made useful progress. As for so many promising lines of research related to bringing aging under medical control, it has been next to impossible to raise funds for this work. The most critical studies in senescent cell clearance, those that proved the case beyond any reasonable doubt, were funded through philanthropy, as is often the case for work at the true cutting edge of medical science. The tipping point has come and gone now, however. At present commercial development is underway. Oisin Biotechnologies and UNITY Biotechnology are building various types of therapy to eliminate senescent cells, and I'm sure they'll be joined by other efforts as more evidence rolls in from animal studies.

Of particular interest in the research results linked here is that tissue elasticity improved. Loss of elasticity is of great importance in the aging of many parts of the body, such as skin and blood vessels. In blood vessels, for example, loss of elasticity leads to hypertension which causes cardiovascular disease and then death. It remains an open question as to which of the primary forms of cell and tissue damage are more important in this process of stiffening. If senescent cell clearance helps meaningfully for blood vessels, then we should all be very thankful, as therapies to remove senescent cells will be arriving in the clinic years in advance of rejuvenation treatments that can address other likely causes of loss of elasticity, such as persistent cross-link formation in the extracellular matrix.

The method of senescent cell elimination that the scientists employed in this study is not something that can be turned into a therapy, since it depends on creating a genetically altered lineage of mice, in which cells are primed to accept a self-destruct trigger that operates only on senescent cells. Its utility lies in the ability to remove senescent cells precisely in a given tissue, and at a given time. That precision means that researchers can be more certain that senescent cell clearance is the cause of the observed benefits. Given the growing number of ways to target senescent cells for clearance that can be turned into human therapies, it is fortunately not an issue that the experimental tests are using a more restricted approach. Removal of these cells is the important target, and any safe and effective methodology should do the job just fine.

Elimination of p19ARF-expressing cells enhances pulmonary function in mice

While there is no doubt that cellular senescence prevents cancer, an increasing amount of evidence suggests that cellular senescence is involved in other biological processes and pathologies. Cellular senescence has been shown to contribute to embryonic development, wound healing, and tissue regeneration. Additionally, it has become more evident that cellular senescence contributes to tissue aging. Senescent cells accumulate in many tissues during aging and are considered to underlie aging-associated pathologies. The contribution of senescent cells in aging-associated phenotypes may depend on signaling, such as senescence-associated secretory phenotype (SASP), because the population of senescent cells is very small, even in very old human tissue.

Two major tumor suppressor pathways, namely, the p19ARF (p14ARF in humans)/p53 and p16INK4a/Rb pathways, play critical roles in the induction and maintenance of cell cycle arrest during cellular senescence. In the present study, we established a transgenic model from which it was possible to eliminate p19ARF-expressing cells using a toxin-mediated cell knockout system. Similar to INK4a, the expression of ARF has been shown to increase during aging in the mouse. Using the transgenic model, we successfully eliminated ARF-expressing cells from the lung tissue of 12-month-old animals. The ablation of ARF expression abolished the expression of other senescent markers, including INK4a and p21, suggesting that the expression of ARF reflects the accumulation of senescent cells in tissues. The elimination of p19ARF-expressing cells in lung tissue ameliorates the aging-associated loss of tissue elasticity. Moreover, the expression of a large number of aging-associated genes was reversed after the removal of p19ARF-expressing cells. Taken together, these findings highlight the role of p19ARF in lung tissue aging and indicate that the aging phenotype in lung tissue may be reversed by eliminating p19ARF-expressing cells from tissue.

Senescent cells are known to have an effect on their surrounding "nonsenescent" cells through SASP. Our results suggest that the population of p19ARF-expressing cells was very small, even in adult lung tissue (approximately 1% of the lung mesenchymal population). Nevertheless, our microarray data indicate that these "rare" p19ARF-expressing cells strongly influence gene expression in lung tissue. Hundreds of genes are upregulated and downregulated during aging in the lung, and more than half of these aging-associated genes show p19ARF dependence. Since senescent cells induce senescence-like gene expression in their surrounding cells through SASP, it is reasonable to assume that changes in aging-associated genes in lung tissue do not simply reflect the events within p19ARF-expressing cells, but also include global changes in lung tissue cells that are mostly nonsenescent.

We performed pulmonary function tests on these mice. Static lung compliance (Cst) was significantly higher in older animals than in young animals. The treatment resulted in the marked recovery of lung elasticity (decrease in Cst). Similarly, the treatment reversed aging-associated changes in dynamic compliance, dynamic resistance, tissue elastance, and tissue damping. These results clearly indicated that the p19ARF-expressing cells that accumulated in 12-month-old lung tissue had deleterious effects on pulmonary function and that aging-associated declines in pulmonary function were ameliorated by the elimination of these p19ARF-expressing cells. We also examined the effects of ARF-expressing cell elimination on even older animals. Tumor-free female mice between 20 and 22 months old were treated 1 month. Pulmonary function tests revealed that tissue compliance in older mice was similar to that in 12-month-old mice. The treatment reduced tissue compliance in older animals; however, this effect was less than that observed in 12-month-old mice. Collectively, these results indicated that p19ARF-expressing cells provoked the loss of elastic fibers in lung tissue and were also responsible for the increase in lung compliance in aged animals.

Comments

If Unity or Oisin are hoping for a cosmetic effect on the skin for their treatments, then this observation of improved elasticity in mouse lungs is a positive.

I wonder if the turnover of collagen and elastic fibers is similar in mice and humans?

Posted by: Jim at August 4th, 2016 10:37 PM

That's what I was thinking, Jim. There is loads of money to be earned in the skin care industry, so skin therapies should be one of the first rejuvenation therapies on the market.

Posted by: Denis at August 5th, 2016 7:19 AM

I hope this pans out for arterial elasticity. It'd be nice not to have to take BP medicines anymore, side effects are hard to live with.

Posted by: bmack500 at August 5th, 2016 11:47 AM

"The method of senescent cell elimination that the scientists employed in this study is not something that can be turned into a therapy, since it depends on creating a genetically altered lineage of mice, in which cells are primed to accept a self-destruct trigger that operates only on senescent cells."

When can we create a genetically engineered lineage of humans with the same thing?

Posted by: Slicer at August 5th, 2016 4:06 PM

I wonder if this could lead to therapies that can repair lung damage due to smoking.

Posted by: tlo120 at August 5th, 2016 5:21 PM

Good news! I will double my Quercetin intake from 500mg EOD to 500 mg every day.

@tlo120, advanced COPD Would not be helped much by removing scenscent cells

Posted by: JohnD at August 6th, 2016 4:27 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.