Normal human cells can only divide a limited number of times before they become senescent, where they lose their ability to divide and lose function. Scientific evidence points to a link between cellular senescence and aging in vivo. Thus, a research front is directed at developing antisenescence agents. Even a small percentage of senescent cells may interfere with tissue homeostasis and function. Of the many reported agents that delay cellular senescence, we found methylene blue (MB) to be the most effective. In addition, MB increased the activity of key mitochondrial functions and restored the age-related decline in learning memory and muscle strength of old mice at very low dose. The findings of our studies support further investigations into the mechanism by which MB delays the cellular senescence. Thus, we will measure how and when MB alters specific biochemical and physiological mechanisms of cellular senescence. The proposed research will investigate our hypothesis that MB delays cellular senescence by improving specific functions including, Sirtuins, AMPK, telomeres and by increasing the biogenesis of specific mitochondrial components. To test this hypothesis, we will pursue the following experimental rationale: To treat young and old IMR90 cells with MB and determine the biochemical and physiological changes to key mechanisms of cellular senescence such as telomeres, sirtuins, Nrf2, and oxidative metabolism. We will also study the time-dependence of the effect of MB on young and old IMR90 cells. In order to investigate for additional effects of MB we will perform gene profiling to expand our understanding for the molecular response to MB. We will use human normal fibroblasts (IMR90). The clinical significance of this project is viewed through MB's potential to prevent or delay age-related disorders in human. Clinical trials on human using MB are feasible because MB is a familiar drug that has several important medicinal uses. Thus, the safety of MB in these settings is well-established.

Public Health Relevance

We found that the drug methylene blue (MB) exhibits anti-senescence and anti-aging activities that can be demonstrated in vitro and in vivo. We also found that MB restores the spatial memory and cognitive decline in old mice. We are investigating the mechanism by which MB delays cell senescence. We also are investigating the effect of MB on specific mitochondrial functions, biogenesis, and redox metabolism. Because MB is an FDA approved drug with established use in human, this research will set the stage for future clinical trials to lower the risk of age-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15AG041414-01
Application #
8231060
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2011-09-30
Budget End
2014-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$313,836
Indirect Cost
Name
Commonwealth Medical College
Department
Type
DUNS #
825062677
City
Scranton
State
PA
Country
United States
Zip Code
18509
Atamna, Hani; Brahmbhatt, Marmik; Atamna, Wafa et al. (2015) ApoHRP-based assay to measure intracellular regulatory heme. Metallomics 7:309-21
Atamna, Hani; Atamna, Wafa; Al-Eyd, Ghaith et al. (2015) Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue. Redox Biol 6:426-35
Atamna, Hani; Mackey, Jeanette; Dhahbi, Joseph M (2012) Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction. Biofactors 38:158-66