The biology of telomeres and telomerase has been the subject of intensive investigative effort since it became evident that they play a significant role in two important biological processes, the loss of cellular replicative capacity inherent to organismal ageing and the unrestricted cell proliferation characteristic of carcinogenesis. Telomere shortening in normal cells is a result of DNA replication events, and reduction beyond a critical length is a signal for cellular senescence.
Particulate drug carriers offer unique opportunities to improve tumor therapy through several different mechanisms. Liposomes may (1) assist in formulation of poorly-soluble therapeutic agents, (2) provide a slow-release vehicle to achieve pharmacokinetic profiles that maximize the therapeutic index, or (3) behave as long-circulating nano-particulates that can extravasate in the hyperpermeable regions of tumor vasculature. For paclitaxel, liposomes provide an aid to formulation.
PURPOSE: Telomeres are specialized DNA-protein complexes found at the ends of eukaryotic chromosomes. In normal somatic cells these become shorter with each cell division and appear to control their replicative lifespan. However almost all tumours show activation of the enzyme telomerase, a specialised reverse transcriptase/DNA polymerase, that can add new telomeric repeats to the ends of chromosomes and this appears to be a key factor in the cell immortalization process.
With the aim of up-regulating antitumor efficacy and down-regulating adverse effects, three types of aromatic imide and diimides were designed to couple with different polyamines. The in vitro assays revealed that two naphthalene diimide-polyamine conjugates could inhibit the growth of multiple cancer cell lines more potently than amonafide. 9f, the most potent compound, was verified to efficiently induce apoptosis via a ROS mediated mitochondrial pathway in a preliminary mechanistic study.
Macroautophagy is a self-cannibalistic process that enables cells to adapt to various stresses and maintain energy homeostasis. Additionally, autophagy is an important route for turnover of misfolded proteins and damaged organelles, with important implications in cancer, neurodegenerative diseases and aging. Resveratrol and spermidine are able to induce autophagy by affecting deacetylases and acetylases, respectively, and have been found to extend the life-span of model organisms.
Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans.
The mTOR [mammalian (or mechanistic) target of rapamycin] protein kinase co-ordinates catabolic and anabolic processes in response to growth factors and nutrients and is a validated anticancer drug target. Rapamycin and related allosteric inhibitors of mTORC1 (mTOR complex 1) have had some success in specific tumour types, but have not exhibited broad anticancer activity, prompting the development of new ATP-competitive mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2.
Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association
The French paradox is a dietary anomaly which has focused attention on the Mediterranean diet. Epidemiological studies revealed that this diet, replete in flavonoid-rich foods (Allium and Brassica vegetables, and red wine), correlated with the increased longevity and decreased incidence of cardiovascular disease seen in these populations. The most frequently studied flavonoid, quercetin, has been shown to have biological properties consistent with its sparing effect on the cardiovascular system.
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effect of caloric restriction is due to decreasing IGF-1 levels.
Dietary or calorie restriction (DR, CR), defined as reduced food intake without malnutrition, imparts many benefits in model organisms. Extended longevity is the most popularized benefit but the least clinically relevant due to the requirement for long-term food restriction. DR also promotes stress resistance and metabolic fitness. Emerging data in experimental models and in humans indicate that these benefits occur rapidly upon initiation of DR, suggesting potential clinical relevance.