In the age that we live in, the world is obsessed with youthfulness. Look around at the individuals that grace our screens and billboards and the glorification of youthfulness is plain to see. However, despite our deep dislike of the topic of aging, it is an unavoidable biological reality for us all.
A Chinese saying goes something like this: that the 4 inescapable realities of life are “birth, aging, disease, and death.” Perhaps a little macabre in its translation into English, but it makes an important point about the typical stages of the average life. The statement that “aging” precedes “disease” in the Chinese saying is particularly interesting; an abundance of research today tells us that the aging process does indeed trigger biological pathways that predispose one to illness.
Cellular senescence is the term given to describe the deterioration of cellular structure and functions due to aging. It contributes to the macromolecular damage and metabolic dysregulation that characterizes many diseases, including idiopathic pulmonary fibrosis (IPF).
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Researchers from Texas described the processes of cellular senescence, particularly in relation to IPF, in Current Molecular Biological Reports. It is their report that we will explore in this article today.
Cellular Senescence: Biological Aging
Cellular senescence and its impact on age-related disorders have garnered increasing attention over the years. The authors of the study characterized cellular senescence as the “stress-induced, nonreversible cell cycle arrest, which depletes regenerative capability and is associated with release of proinflammatory mediators.”
Cellular senescence is associated with the pathophysiology of a number of diseases, such as IPF, Alzheimer’s disease, and osteoarthritis, due to the ability of senescent cells to arrest the growth of previously replicative cells, express antiproliferative molecules, and trigger damage-sensing signaling pathways.
Read an overview of IPF
In normal situations, these functions of cellular senescence can counter the proliferation of malignant cells. Over time, cells accumulate damage and undergo apoptosis or senescence to prevent their accumulation in the body. “However, the generation and maintenance of senescent cells by activation of prosurvival pathways may outpace immune clearance, which creates self-expanding reservoirs of senescent cells and can ultimately lead to clinical disease,” the authors of the study explained.
What induces cellular senescence in cellular aging? There are a few well-known culprits. Telomere shortening, which occurs with age, predisposes cells to DNA damage. Other possible causes of DNA damage are ionizing radiation and genotoxic agents. DNA damage, in turn, drives cellular senescence.
In layman’s terms, cellular senescence can be described simply as “aging.” It causes external symptoms deeply associated with aging, such as the greying of hair, loss of muscle mass, and weakening of mental faculties. Internally, cellular senescence is implicated in diminishing the function of stem cells and senescent endothelial cells, as well as in altering the extracellular matrix. A relatively tiny reservoir of senescent cells can cause an outsized effect on tissue function and integrity.
Proposed Therapies
There is increasing interest in counteracting the pathological functions of cellular senescence. In IPF, cellular senescence has been theorized to be heavily involved in chronic matrix remodeling and fibrosis. Therefore, therapies targeting cellular senescence can potentially reverse some of the pathological features of IPF and other age-related disorders.
Two methods have been proposed:
- Senolytics: senescent-selective apoptosis
- Senomorphics: suppression of senescence-associated secretory phenotype (SASP)
Much research is currently being conducted to improve our understanding of both of these therapies. For now, we do know that one key benefit of the senolytic approach is that intermittent treatment is effective in reducing senescent reservoirs. This means that continuous treatment can be avoided, thus reducing the treatment burden on patients and mitigating any potential adverse effects.
Read more about IPF prognosis
The senomorphic approach, on the other hand, likely requires continuous treatment to allow for the proliferation of physiologic senescent cells and the suppression of pathogenic ones. The study authors stated, “Combination therapy consisting of senolytic induction treatment with subsequent senomorphic maintenance treatment has been proposed by our group.”
Senotherapeutics have also been trialed in treating IPF. Although senomorphics have not been studied in patients with IPF yet, we do have a few studies on senolytic therapies. Patients with IPF treated with intermittent dasatinib and quercetin (DQ), a senolytic combination therapy, have demonstrated significant physical improvements across various parameters, including the 6-minute walk test, 4-minute gait speed, short physical performance battery, and timed chair stands. In addition, DQ therapy was generally well tolerated.
DQ therapy has also shown promising results in other studies. In bleomycin-induced fibrosis mouse models, DQ demonstrated significant improvements in senescent burden, pulmonary function, and physical function. Researchers have also demonstrated the ex vivo senolysis of lung fibroblasts and alveolar epithelial cells.
Could Aging One Day Be Reversed?
We return to the age-old question that has haunted humanity throughout history: can aging be reversed? Can humans indeed live forever, in a perpetual state of youthfulness?
Current research seems to indicate that while this is not possible (yet), attempts to terminate pathological aging-related pathways may be within reach, which would have the effect of slowing down the effects of aging. Perhaps the ultimate answer to where the elixir of life can be found is not in some far and mysterious land, but in labs all across the world in which researchers are working hard to create new therapies for aging-related pathologies.
References
Kellogg DL, Kellogg DL Jr, Musi N, Nambiar AM. Cellular senescence in idiopathic pulmonary fibrosis. Curr Mol Biol Rep. Published online August 12, 2021. doi:10.1007/s40610-021-00145-4
Heukels P, Moor CC, von der Thüsen JH, Wijsenbeek MS, Kool M. Inflammation and immunity in IPF pathogenesis and treatment. Respir Med. 2019;147:79-91. doi:10.1016/j.rmed.2018.12.015
