Dasatinib and quercetin increase testosterone and sperm concentration in mice.

Cellular senescence is a defense mechanism to arrest proliferation of damaged cells. The number of senescent cells increases with age in different tissues and contributes to the development of age-related diseases. Old mice treated with senolytics drugs, dasatinib and quercetin (D+Q), have reduced senescent cells burden. The aim of this study was to evaluate the effects of D+Q on testicular function and fertility of male mice. Mice (n = 9/group) received D (5 mg kg-1) and Q (50 mg kg-1) via gavage every moth for three consecutive days from 3 to 8 months of age. At 8 months mice were breed with young non-treated females and euthanized. The treatment of male mice with D+Q increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology. Sperm motility, seminiferous tubule morphometry, testicular gene expression and fertility were not affected by treatment. There was no effect of D+Q treatment in β-galactosidase activity and in lipofuscin staining in testes. D+Q treatment also did not affect body mass gain and testes mass. In conclusion, D+Q treatment increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology, however did not affect fertility. Further studies with older mice and different senolytics are necessary to elucidate the effects in the decline of sperm output (quality and quantity) associated with aging.

[1]  D. Gems,et al.  Is “cellular senescence” a misnomer? , 2022, GeroScience.

[2]  A. Schneider,et al.  17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs. , 2022, GeroScience.

[3]  M. Masternak,et al.  Senolytic treatment reverses obesity-mediated senescent cell accumulation in the ovary , 2022, GeroScience.

[4]  A. Mylonas,et al.  Cellular Senescence and Ageing: Mechanisms and Interventions , 2022, Frontiers in Aging.

[5]  Kevin A. Murach,et al.  Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice , 2021, Aging cell.

[6]  Victor A. Ansere,et al.  Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion , 2020, Mechanisms of Ageing and Development.

[7]  Vasudha Katragadda,et al.  Testosterone recuperates deteriorated male fertility in cypermethrin intoxicated rats , 2020, Toxicological Research.

[8]  H. Deng,et al.  Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice , 2020, Cell Research.

[9]  Luc J. Martin,et al.  Improvement of Testicular Steroidogenesis Using Flavonoids and Isoflavonoids for Prevention of Late-Onset Male Hypogonadism , 2020, Antioxidants.

[10]  T. Morais,et al.  Caloric restriction alters the hormonal profile and testicular metabolome resulting in alterations of sperm head morphology. , 2019, American journal of physiology. Endocrinology and metabolism.

[11]  C. Schmitt,et al.  Cellular Senescence: Defining a Path Forward , 2019, Cell.

[12]  A. Bartke,et al.  Effect of caloric restriction and rapamycin on ovarian aging in mice , 2019, GeroScience.

[13]  P. Robbins,et al.  SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs. , 2019, Journal of visualized experiments : JoVE.

[14]  S. Kritchevsky,et al.  Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study , 2019, EBioMedicine.

[15]  D. Allison,et al.  Senolytics Improve Physical Function and Increase Lifespan in Old Age , 2018, Nature Medicine.

[16]  Y. Suh,et al.  Age- and Tissue-Specific Expression of Senescence Biomarkers in Mice , 2018, Front. Genet..

[17]  M. Alves,et al.  Mammalian target of rapamycin (mTOR): a central regulator of male fertility? , 2017, Critical reviews in biochemistry and molecular biology.

[18]  M. Nistal,et al.  Testicular Changes in Elderly Men , 2017 .

[19]  V. Gorgoulis,et al.  Sudan Black B, The Specific Histochemical Stain for Lipofuscin: A Novel Method to Detect Senescent Cells. , 2017, Methods in molecular biology.

[20]  Kathleen F. Kerr,et al.  Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice , 2016, eLife.

[21]  Subramani Parasuraman,et al.  Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid , 2016, Pharmacognosy reviews.

[22]  Sajal Gupta,et al.  Hypoosmotic Swelling Test (HOS) , 2016 .

[23]  Zhengrong Xia,et al.  Expression of Flotilin-2 and Acrosome Biogenesis Are Regulated by MiR-124 during Spermatogenesis , 2015, PloS one.

[24]  N. LeBrasseur,et al.  The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs , 2015, Aging cell.

[25]  A. Fisher,et al.  Advancing age increases sperm chromatin damage and impairs fertility in peroxiredoxin 6 null mice , 2015, Redox biology.

[26]  R. Baruffi,et al.  The effects of age on sperm quality: an evaluation of 1,500 semen samples , 2014, JBRA assisted reproduction.

[27]  W. Walker,et al.  The regulation of spermatogenesis by androgens. , 2014, Seminars in cell & developmental biology.

[28]  Manuel Serrano,et al.  The Hallmarks of Aging , 2013, Cell.

[29]  J. Campisi,et al.  Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. , 2013, The Journal of clinical investigation.

[30]  G. Kaushik,et al.  Quercetin impairs the reproductive potential of male mice , 2013, Andrologia.

[31]  J. Bartek,et al.  Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues , 2012, Aging.

[32]  R. Jeyendran,et al.  The hypo-osmotic swelling test for evaluation of sperm membrane integrity. , 2013, Methods in molecular biology.

[33]  D. Sibley,et al.  The Blood-Testis Barrier and Its Implications for Male Contraception , 2012, Pharmacological Reviews.

[34]  R. Meacham,et al.  Fertility and the aging male. , 2011, Reviews in urology.

[35]  D. Ingram,et al.  Effects of Moderate Calorie Restriction on Testosterone Production and Semen Characteristics in Young Rhesus Macaques (Macaca mulatta)1 , 2010, Biology of reproduction.

[36]  M. Nouri,et al.  Beneficial effects of quercetin on sperm parameters in streptozotocin‐induced diabetic male rats , 2010, Phytotherapy research : PTR.

[37]  C. Kenyon The genetics of ageing , 2010, Nature.

[38]  A. Agarwal,et al.  Free radical theory of aging: implications in male infertility. , 2010, Urology.

[39]  L. Martorana,et al.  Gynecomastia in a male after dasatinib treatment for chronic myeloid leukemia , 2008, Leukemia.

[40]  B. Zirkin,et al.  Aging and caloric restriction: Effects on Leydig cell steroidogenesis , 2005, Experimental Gerontology.

[41]  R. Braun,et al.  Androgen receptor function is required in Sertoli cells for the terminal differentiation of haploid spermatids , 2003, Development.

[42]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[43]  K. Tung,et al.  Role of testicular autoantigens and influence of lymphokines in testicular autoimmune disease. , 1990, Journal of reproductive immunology.