Dr. Ron’s Research Review – February 24, 2016

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This week’s research review focuses on senescence.

Senescence (Latin: to grow old) or biological aging is the gradual deterioration of function characteristic of most complex life.
Cellular senescence refers to the phenomenon by which normal diploid cells cease to divide. The Hayflick limit is the number of times a normal human cell population will divide until cell division stops (about 50). (Watts, 2011)
The Hayflick limit has been found to correlate with telomeres, the repeating DNA sequences at the tip ends of the chromosomes. Every time a cell divides the telomeres become shorter. Eventually they become too short to allow replication, which may lead to chromosome instability or cell death. The enzyme telomerase adds repeating sequences to the ends of the chromosomes. (Axelrad et al., 2013)
Senotherapeutics refers to therapeutic agents and strategies that specifically target cellular senescence. A senolytic (from "senescence" and "lytic" - destroying) is among the class of seno-therapeutics that refers to small molecules that can selectively induce death of senescent cells.
There are several senotherapeutic agents.
Quercitin (Zhu et al., 2015) (Malavolta et al., 2015)
Tocotrienols (Malavolta et al., 2015)
Carnosine (Wang et al., 2000) (McFarland and Holliday, 1994)
Vitamin C (Kim et al., 2008)
Vitamin D (Marampon et al., 2015)
Vitamin A (Morgan and Simms, 1939)
Fucoidan (Min et al., 2014)
Berberine (Zhao et al., 2013)
Ghrelin (Yin and Zhang, 2015)

Dr. Ron


Articles

 

Pleiotropic effects of tocotrienols and quercetin on cellular senescence: introducing the perspective of senolytic effects of phytochemicals.
            (Malavolta et al., 2015) Download
The possibility to target cellular senescence with natural bioactive substances open interesting therapeutic perspective in cancer and aging. Engaging senescence response is suggested as a key component for therapeutic intervention in the eradication of cancer. At the same time, delaying senescence or even promote death of accumulating apoptosis-resistant senescent cells is proposed as a strategy to prevent age related diseases. Although these two desired outcome present an intrinsic dichotomy, there are examples of promising natural compounds that appear to satisfy all the requirements to develop senescence-targeted health promoting nutraceuticals. Tocotrienols (T3s) and quercetin (QUE), albeit belonging to different phytochemical classes, display similar and promising effects "in vitro" when tested in normal and cancer cells. Both compounds have been shown to induce senescence and promote apoptosis in a multitude of cancer lines. Conversely, they display senescence delaying activity in primary cells and rejuvenating effects in senescent cells. More recently, QUE has been shown to display senolytic effects in some primary senescent cells, likely as a consequence of its inhibitory effects on specific anti-apoptotic genes (i.e. PI3K and other kinases). Senolytic activity has not been tested for T3s but part of metabolic and apoptotic pathways affected by these compounds in cancer cells overlap with those of QUE. This suggests that the rejuvenating effects of T3s and QUE on pre-senescent and senescent primary cells might be the net results of a senolytic activity on senescent cells and a selective survival of a sub-population of non-senescent cells in the culture. The meaning of this hypothesis in the context of adjuvant therapy of cancer and preventive anti-aging strategies with QUE or T3s is discussed.

Use of carnosine as a natural anti-senescence drug for human beings.
            (Wang et al., 2000) Download
Carnosine is an endogenous free-radical scavenger. The latest research has indicated that apart from the function of protecting cells from oxidation-induced stress damage, carnosine appears to be able to extend the lifespan of cultured cells, rejuvenate senescent cells, inhibit the toxic effects of amyloid peptide (A beta), malondialdehyde, and hypochlorite to cells, inhibit glycosylation of proteins and protein-DNA and protein-protein cross-linking, and maintain cellular homeostasis. Also, carnosine seems to delay the impairment of eyesight with aging, effectively preventing and treating senile cataract and other age-related diseases. Therefore, carnosine may be applied to human being as a drug against aging.

The Role of Ghrelin in Senescence: A Mini-Review.
            (Yin and Zhang, 2015) Download
Ghrelin, a 28-amino acid hormone produced mainly by the X/A-like endocrine cells in gastric mucosa, has a widespread tissue distribution and diverse physiological functions such as hormonal, orexigenic, metabolic, cardiovascular, neurological, and immunological activities. Considerable evidence has suggested that ghrelin plays an important role in organism senescence or aging. The present review provides a comprehensive picture of this new development. We first reviewed the aging (senescence)-dependent reduction of ghrelin signaling, and then highlighted its relationship with the aging-associated alteration in food intake, energy metabolism, cardiovascular function, neurological activity, and adaptive immunity. Our literature review suggests that ghrelin is an innovative and promising agent in the treatment of these pathophysiological conditions associated with senescence. © 2015 S. Karger AG, Basel.

The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.
            (Zhu et al., 2015) Download
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 the 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 same 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 disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

 

 

References

Axelrad, MD, T Budagov, and G Atzmon (2013), ‘Telomere length and telomerase activity; a Yin and Yang of cell senescence.’, J Vis Exp, (75), e50246. PubMed: 23728273
Kim, JE, et al. (2008), ‘Vitamin C inhibits p53-induced replicative senescence through suppression of ROS production and p38 MAPK activity.’, Int J Mol Med, 22 (5), 651-55. PubMed: 18949386
Malavolta, M, et al. (2015), ‘Pleiotropic effects of tocotrienols and quercetin on cellular senescence: introducing the perspective of senolytic effects of phytochemicals.’, Curr Drug Targets, PubMed: 26343116
Marampon, F, et al. (2015), ‘Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis.’, J Endocrinol Invest, PubMed: 26335302
McFarland, GA and R Holliday (1994), ‘Retardation of the senescence of cultured human diploid fibroblasts by carnosine.’, Exp Cell Res, 212 (2), 167-75. PubMed: 8187813
Min, EY, et al. (2014), ‘The effects of fucodian on senescence are controlled by the p16INK4a-pRb and p14Arf-p53 pathways in hepatocellular carcinoma and hepatic cell lines.’, Int J Oncol, 45 (1), 47-56. PubMed: 24807532
Morgan, AF and HD Simms (1939), ‘Adrenal Atrophy And Senescence Produced By A Vitamin Deficiency.’, Science, 89 (2320), 565-66. PubMed: 17741477
Wang, AM, et al. (2000), ‘Use of carnosine as a natural anti-senescence drug for human beings.’, Biochemistry (Mosc), 65 (7), 869-71. PubMed: 10951108
Watts, G (2011), ‘Leonard Hayflick and the limits of ageing.’, Lancet, 377 (9783), 2075. PubMed: 21684371
Yin, Y and W Zhang (2015), ‘The Role of Ghrelin in Senescence: A Mini-Review.’, Gerontology, PubMed: 26160147
Zhao, H, et al. (2013), ‘Berberine suppresses gero-conversion from cell cycle arrest to senescence.’, Aging (Albany NY), 5 (8), 623-36. PubMed: 23974852
Zhu, Y, et al. (2015), ‘The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.’, Aging Cell, 14 (4), 644-58. PubMed: 25754370