The research results noted here today are most interesting, as the scientists involved report success in turning back a number of measures of cardiovascular and general aging in old rats via delivery of cells derived from young heart tissue. This work touches on a whole range of themes from recent years: cell therapies involving transplants from young to old individuals; that cell therapies might produce the bulk of their beneficial effects through cell signaling; the degree to which vesicles are the important channel for that cell signaling; the role of cellular senescence in the processes of tissue aging, such as rising levels of fibrosis; and to round out the selection, considerations of telomere dynamics and telomerase activity. It is a fairly impressive collection of important topics for just the one study.
To me the the point that stands out is that senescent cells were reduced in number following treatment. I would like to know whether this happens because signaling from the transplanted cells pushes these lingering senescent cells across the line into self-destruction via apoptosis, or whether it spurs the immune system to destroy them, though I imagine I'll be waiting a few years to find out. Most of the metrics mentioned in the paper could be explained by reduction in senescent cell count, as via the senescence-associated secretory phenotype (SASP), these unwanted cells are directly responsible for chronic inflammation, fibrosis, disruption of regeneration, and possibly cardiac hypertrophy. The evidence for those consequences of cellular senescence has amassed in numerous papers over the past few years. We should also expect senescent cells to contribute meaningfully to many or most of the other aspects of aging in similar ways.
We might speculate on the size of the senolytic contribution in this study versus that of increased telomerase and consequent changes in average telomere length. While there are examples of increased telomerase producing benefits to health and longevity in rodent studies, it has to be noted that rodent telomere dynamics are very different from those of humans. For one, rodents express telomerase in somatic cells, whereas humans do not. So it isn't at all clear what the telomere and telomerase observations here mean when it comes to predicting outcomes in humans. It is possible to suggest that additional telomerase and telomere lengthening in stem cells may have analogous effects, as the situation in rodents and humans for stem cell telomere dynamics is less radically different. But for an observation of increased telomerase in somatic cells? Hard to say.
That said, this is a very promising study that opens many doors for further exploration. What in the vesicles is acting as a senolytic therapy to remove senescent cells? Might this behavior be found in other cell types, and can it be generalized, identified, and recreated to order via cell programming techniques? To what degree are the results shown in this study due to reduced burden of cellular senescence versus consequences of increased telomerase versus other possible mechanisms? Is there a useful shortcut in all of this to human cell therapies that will have more of an effect on the underpinnings of aging than those developed to date? These and other, similar questions spring to mind immediately.
In the study, investigators injected cardiosphere-derived cells, a specific type of stem cell known as CDCs, from newborn laboratory rats into the hearts of rats with an average age of 22 months, which is considered aged. Other laboratory rats from the same age group were assigned to receive placebo treatment, saline injections instead of stem cells. Both groups of aged rats were compared to a group of young rats with an average age of 4 months. Baseline heart function was measured in all rats, using echocardiograms, treadmill stress tests, and blood analysis. The older rats underwent an additional round of testing one month after receiving cardiosphere-derived cells that came from young rats.
"The way the cells work to reverse aging is fascinating. They secrete tiny vesicles that are chock-full of signaling molecules such as RNA and proteins. The vesicles from young cells appear to contain all the needed instructions to turn back the clock." Results of those tests show lab rats that received the cardiosphere-derived cells experienced the following: improved heart function; demonstrated longer heart cell telomeres; improved their exercise capacity by an average of approximately 20 percent; and regrew hair faster than rats that didn't receive the cells. "This study didn't measure whether receiving the cardiosphere-derived cells extended lifespans, so we have a lot more work to do. We have much to study, including whether CDCs need to come from a young donor to have the same rejuvenating effects and whether the extracellular vesicles are able to reproduce all the rejuvenating effects we detect with CDCs."
Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated. We compared intra-cardiac injections of neonatal rat CDCs to a control of phosphate-buffered saline, PBS, in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats of 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitor cells from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs from paediatric donors.
Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed). Telomeres in heart cells were longer in CDC-transplanted animals. Cardiosphere-derived cells attenuated hypertrophy; histology confirmed decreases in cardiomyocyte area and myocardial fibrosis. Cardiosphere-derived cell injection improved diastolic dysfunction compared with baseline, and lowered serum brain natriuretic peptide. In CDC-transplanted old rats, exercise capacity increased ∼20%, body weight decreased ∼30% less, and hair regrowth after shaving was more robust. Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group. In summary, young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture.