The progression of physiological aging is driven by intracellular mutation, including but not limited to telomere attrition, genomic instability, epigenetic alterations, oxidative stress, toxemia, loss of proteostasis and, inter alia, cellular senescence.
Cellular senescence, a state of irreversible cell cycle arrest, is a robust mechanism used to mediate tumor suppression and control the tissue damage response. These senescent cells can upregulate specific immune ligands on their cell surface that can mediate the recognition of these cells by specific immune cell subsets and lead to activation of the immune cells. It is hypothesized that that cellular senescence evolved as a cancer barrier since non-proliferating senescent cells cannot be transformed to neoplastic cells. On the other hand senescent cells favor cancer development, just like other age-related pathologies, by creating a low grade inflammatory state due to senescence associated secretory phenotype (SASP). (Exhibit A). Reversal/inhibition of cellular senescence could prolong healthy life span, thus many attempts have been undertaken to influence cellular senescence. The two main approaches are genetic and pharmacological/nutritional modifications of cell fate.
To this end, a new study has proven from from animal experiments that senolytics — a new class of drugs that selectively kill senescent cells — might dramatically slow the aging process and extend health during the lifespan. In experiments where scientists kill senescent cells in mice, the small rodents’ time where they live free of disease (healthspan) is lengthened and enhanced. (See Exhibit B).
In conducting these studies, it was discovered was senescent cells have a greater expression of pro-survival mechanisms and, just like cancer cells, these up-regulated mechanisms help the cells resist programmed death (apoptosis).
Having made this discovery, the research team worked backward and looked at all the available compounds to see if any interfered with the up-regulation of pro-survival mechanisms in cells. (Professor Weinberg had done the same type of experiements with cancer stem cells). These scientists narrowed down these compounds to the two best candidates. the cancer drug dasatinib (Sprycel) and the holistic supplement, quercetin, a natural molecular that acts as an antihistamine and anti-inflammatory.
Interestingly, with this modern and holistic medicine synergy, dasatinib and quercetin reduced osteoporosis and frailty, improved cardiovascular function as well as endurance, and extended the healthspan of the mice. Within five days of a single dose of the drugs, cardiovascular function was improved in the oldest mice. A single dose of the drug cocktail led to improved exercise capacity (as measured by the mice running on miniature treadmills) with the positive effects lasting for seven months or more. When the drugs were given periodically, the mice demonstrated delayed age-related symptoms, spine degeneration, and osteoporosis.
Human clinical trials would most certainly be warranted. Meanwhile, pending the conclusion of these trials, aging patients can have recourse to holistic geriatric and holistic oncology as quercetin has been one of the key supplements that many health practitioners have used for decades.
Biogerontology. 2014 Dec;15(6):627-42. Senescent cells: SASPected drivers of age-related pathologies. By Ovadya Y1, Krizhanovsky V.
The progression of physiological ageing is driven by intracellular aberrations including telomere attrition, genomic instability, epigenetic alterations and loss of proteostasis. These in turn damage cells and compromise their functionality. Cellular senescence, a stable irreversible cell-cycle arrest, is elicited in damaged cells and prevents their propagation in the organism. Under normal conditions, senescent cells recruit the immune system which facilitates their removal from tissues. Nevertheless, during ageing, tissue-residing senescent cells tend to accumulate, and might negatively impact their microenvironment via profound secretory phenotype with pro-inflammatory characteristics, termed senescence-associated secretory phenotype (SASP). Indeed, senescent cells are mostly abundant at sites of age-related pathologies, including degenerative disorders and malignancies. Interestingly, studies on progeroid mice indicate that selective elimination of senescent cells can delay age-related deterioration. This suggests that chronic inflammation induced by senescent cells might be a main driver of these pathologies. Importantly, senescent cells accumulate as a result of deficient immune surveillance, and their removal is increased upon the use of immune stimulatory agents. Insights into mechanisms of senescence surveillance could be combined with current approaches for cancer immunotherapy to propose new preventive and therapeutic strategies for age-related diseases.
Aging Cell. 2015 Mar 9. The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Zhu Y1, Tchkonia T, Pirtskhalava T, Gower A, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Borden G, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL.
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1-/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1-/∆ mice, delaying age-related symptoms and pathology, osteoporosis and loss of intervertebral disc proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan. This article is protected by copyright. All rights reserved. KEYWORDS: PI3K delta; dasatinib; dependence receptors; ephrins; p21; plasminogen-activated inhibitor; quercetin
Biogerontology. 2013 Dec;14(6):617-28. Immunosurveillance of senescent cells: the bright side of the senescence program. Sagiv A1, Krizhanovsky V.
Cellular senescence, a state of irreversible cell cycle arrest, is a robust mechanism used to mediate tumor suppression and control the tissue damage response following short-term insults. In addition, the senescence associated-secretory phenotype (SASP), one of the most profound characteristics of the senescence program, facilitates the immunosurveillance of senescent cells. The SASP includes many chemokines, cytokines and adhesion molecules that can recruit and activate distinct immune cells from both the innate and adaptive immune system such as NK cells, monocytes/macrophages and T cells. Furthermore, senescent cells can upregulate specific immune ligands on their cell surface that can mediate the recognition of these cells by specific immune cell subsets and lead to activation of the immune cells. Consequently, the activated immune cells engage explicit regulatory mechanisms to eliminate senescent cells. For example, recent work from our laboratory showed that perforin-granzyme exocytosis mediates NK-cell killing of senescent cells. Here, we summarize the current advances in our knowledge of the mechanisms underlying specific immune-mediated elimination of senescent cells.
Exp Gerontol. 2013 Jul;48(7):661-6. Rejuvenation of senescent cells-the road to postponing human aging and age-related disease? Sikora E.
Cellular senescence is the state of permanent inhibition of cell proliferation. Replicative senescence occurs due to the end replication problem and shortening telomeres with each cell division leading to DNA damage response (DDR). The number of short telomeres increases with age and age-related pathologies. Stress induced senescence, although not accompanied by attrition of telomeres, is also attributed to the DDR induced by irreparable DNA lesions in telomeric DNA. Senescent cells characterized by the presence of γH2AX, the common marker of double DNA strand breaks, and other senescence markers including activity of SA-β-gal, accumulate in tissues of aged animals and humans as well as at sites of pathology. It is believed that cellular senescence evolved as a cancer barrier since non-proliferating senescent cells cannot be transformed to neoplastic cells. On the other hand senescent cells favor cancer development, just like other age-related pathologies, by creating a low grade inflammatory state due to senescence associated secretory phenotype (SASP). Reversal/inhibition of cellular senescence could prolong healthy life span, thus many attempts have been undertaken to influence cellular senescence. The two main approaches are genetic and pharmacological/nutritional modifications of cell fate. The first one concerns cell reprogramming by induced pluripotent stem cells (iPSCs), which in vitro is effective even in cells undergoing senescence, or derived from very old or progeroid patients. The second approach concerns modification of senescence signaling pathways just like TOR-induced by pharmacological or with natural agents. However, knowing that aging is unavoidable we cannot expect its elimination, but prolonging healthy life span is a goal worth serious consideration.
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