Aging: past, present and future

Mitochondrial dysfunction and cellsenescence – skin deep into mammalian aging There is a lively discussion going on as to whether oxidative stress is or is not a cause of (accelerated) aging, fuelled to a significant extent by the finding from Arlan Richardson’s group that mice heterozygous for the mitochondrial superoxide dismutase SOD2 showed increased oxidative stress, increased cancer incidence but not accelerated ageing [1]. A new twist to this story was introduced recently when it was shown that connective tissue-specific SOD2 knockouts developed multiple signs of progeria including short lifespan, associated with up-regulation of the cell senescence marker p16INK4A [2]. Mitochondrially generated oxidative stress is both an established cause [3] and a relevant consequence [4] of cell senescence, frequencies of senescent cells in connective tissue increase during mice aging [5], and destruction of senescent cells can ‘cure’ some age-related tissue dysfunction [6]. A paper by Judit...

Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency Abstract Nuclear reprogramming enables patient-specific derivation of induced pluripotent stem (iPS) cells from adult tissue. Yet, iPS generation from patients with  type 2 diabetes  (T2D) has not been demonstrated. Here, we report reproducible iPS derivation of epidermal keratinocytes (HK) from elderly T2D patients. Transduced with human OCT4, SOX2, KLF4 and c-MYC stemness factors under serum-free and feeder-free conditions, reprogrammed cells underwent dedifferentiation with mitochondrial restructuring, induction of endogenous pluripotency genes - including NANOG, LIN28, and TERT, and down-regulation of cytoskeletal, MHC class I- and apoptosis-related genes. Notably, derived iPS clones acquired a rejuvenated state, characterized by elongated telomeres and suppressed senescence-related p15 INK4b /p16 INK4a  gene expression and oxidative stress signal...

Antidepressants synergize with chemotherapy against cancerstem cells  In a recent report [1], the antidepressant drug desmethylclomipramine has shown an interesting synergistic effect with cisplatin, gemcitabine or placlitax on lung cancer stem cells. The fact that antidepressant drugs potentiate chemotherapy in poorly responding cancer is of major relevance, and opens up potential innovative therapeutic effects. But what are the underlying molecular mechanisms for this therapy? Can this be transferred to other poorly responding cancers? We originally identified the HECT containing ITCH as the ubiquitin E3 ligase responsible for the degradation of p63 and p73, and, based on that, we performed an high throughput (HTS) screening using an ELISA-based HTS with purified recombinant proteins and GST-autoubiquitylation as readout for ITCH activity [2]. The automated HTS on a 22,000 compound library was robust, according to an average recorded Z’ of 0.7 (range 0.5-0.7), and resulted in the...

Hormesis does not make sense except in the light of TOR-driven aging Abstract Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two ...

Hypothalamic lipophagy and energetic balance Abstract Autophagy is a conserved cellular turnover process that degrades unwanted cytoplasmic material within lysosomes. Through “in bulk” degradation of cytoplasmic proteins and organelles, including lipid droplets, autophagy helps provide an alternative fuel source, in particular, when nutrients are scarce. Recent work demonstrates a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in regulation of food intake and energy balance. The induction of autophagy in hypothalamic neurons during starvation mobilizes neuronal neutral lipids to generate neuron-intrinsic free fatty acids that serve to upregulate fasting-induced AgRP levels. Blocking autophagy in AgRP neurons in mice reduces fasting-induced food intake, and increases constitutive levels of anorexigenic hypothalamic proopiomelanocortin and its cleavage product α-melanocyte stimulating hormone. The energetic consequences of these molecular events are decreased bo...

Structure-based development of novel sirtuin inhibitors Abstract Sirtuins are NAD + -dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins they deacetylate. The physiological roles of Sirtuins and their potential use as therapeutic targets for metabolic and aging-related diseases have spurred interest in the development of small-molecule Sirtuin modulators. Here, we describe an approach exploiting the structures available for four human Sirtuins for the development of isoform-specific inhibitors. Virtual docking of a compound library into the peptide binding pockets of crystal structures of Sirt2, 3, 5 and 6 yielded compounds potentially discriminating between these isoforms. Further characterization in activity assays revealed several inhibitory compounds with little isoform specificity, but also two compounds with microm...

Longitudinal study of surrogate aging measures during human immunodeficiency virus seroconversion Abstract Persons living with human immunodeficiency virus (HIV) harbor an increased risk of age-related conditions. We measured changes in telomere length and DNA methylation in the peripheral blood of 31 intravenous drug users, who were followed longitudinally with blood samples pre-HIV (T1), immediately post-HIV (T2; 1.9±1 year from T1), and at a later follow-up time (T3; 2.2±1 year from T2). Absolute telomere length measurements were performed using polymerase chain reaction methods. Methylation profiles were obtained using the Illumina Human Methylation450 platform. Methylation aging was assessed using the Horvath method. Telomere length significantly decreased between T1 and T2 (227±46 at T1 vs. 201±48 kbp/genome at T2, p=0.045), while no differences were observed between T2 and T3 (201±48 at T2 vs. 186±27 kbp/genome at T3, p=0.244). Methylation aging as measured by the age accelerati...