Cells enter a state of senescence in response to reaching the Hayflick limit, or to a toxic environment, or potentially cancerous mutational damage. Near all senescent cells self-destruct, or are destroyed by the immune system. Some linger, however, and when present in even comparatively small numbers relative to normal cells, these senescent cells cause considerable harm via their inflammatory secretions. Thus the targeted destruction of senescent cells via senolytic therapies has been shown to extend healthy life and reverse numerous aspects of aging in mice. Human trials of senolytic treatments are presently underway, and have produced promising initial results.
Researchers here do the public service of combing through the existing literature on senescent cells in aging to assemble in one place all that is presently known on the level of cellular senescence in humans by age and tissue type. The data is fairly consistent, in that rising numbers of senescent cells with age appear throughout the body, but present techniques for assessing senescence clearly need to be improved, given that the numbers vary by measurement strategy.
This is the first study to quantify the association between the magnitude of senescence and chronological age across different human tissue types. A qualitative analysis of the literature identifies a largely positive association between cellular senescence and chronological age; however, the strength of the association differed based on the tissue type, subsection of tissue, and the senescence marker used within and between tissues. The observed differences in the strength of the association between senescence and chronological age between tissue types may be explained by the natural cell turnover rate of tissue which is known to vary widely. However, a tissue-specific response to environmental exposures or different defense mechanisms against cytotoxic stress may also explain this variable senescence level within human tissue types. For example, researchers demonstrated higher numbers of senescent cells in patients who have received chemotherapy.
To date, there is little data available on senescence within different organ systems from the same individual. Articles included in this review that investigated the difference in senescence within tissues of the same organ showed that despite higher senescence within these tissues, the magnitude of senescence differed based on the tissue or cell type. Researches also investigated senescence within individuals using tissue samples from different organs (blood and gut) and demonstrated that the magnitude of senescence was not only variable depending on the tissue assessed but also the marker used to define senescence. Thus, in alignment with the findings of this review, the current evidence would suggest that while cellular senescence is likely to increase with chronological age, the magnitude of senescence can vary from tissue to tissue. How this variation in senescence contributes to the onset of age-related disease is yet to be determined.
This analysis did identify some tissue types (adipose, gut, prostate, and thymus) where senescence was not significantly associated with age. The lack of significance in these tissues could be caused by the limited number of studies investigating senescence and age within these tissues and the smaller sample sizes within these articles. Thus, despite positive correlations the relationship between senescence and age within these tissues requires confirmation through additional studies. On the other hand, adipose and thymus tissue are also postmitotic tissue. Senescence within postmitotic cells, such as neurons, adipose, and skeletal muscle, has been largely overlooked in human research, which is reflected in this current review. This is likely due to a lack of evidence as to whether postmitotic cells can become senescent.
In addition to heterogeneity of senescence between and within tissue samples, senescence varied widely depending on the marker used to detect senescence. Notably, correlation of senescence markers and age differed substantially for proliferation and DNA damage markers. This is thought to be caused by the various other cellular processes these markers are involved in, as proliferation and DNA damage are not specific to the senescent phenotype. Furthermore, production of SA-β-gal does not necessarily indicate senescence either: quiescent cells in culture are also known to express SA-β-gal. Thus, the higher expression of any senescent marker within tissue samples as evidence of senescence must be viewed with caution. These observations are supported here by the pronounced heterogeneity of senescence within the same tissue sample, such as skin and eye, using different senescence markers.