Role of autophagy in aging: The good, the bad, and the ugly.

Autophagy (self-eating) is a conserved catabolic homeostatic process required for cellular metabolic demands by removal of the damaged molecules and organelles and for alleviation of stress initiated by pathology and infection. By such actions, autophagy is essential for the prevention of aging, disease, and cancer. Genetic defects of autophagy genes lead to a host of developmental, metabolic, and pathological aberrations.

Resolving Geroplasticity to the Balance of Rejuvenins and Geriatrins.

According to the cell centric hypotheses, the deficits that drive aging occur within cells by age dependent progressive damage to organelles, telomeres, biologic signaling pathways, bioinformational molecules, and by exhaustion of stem cells. Here, we amend these hypotheses and propose an eco-centric model for geroplasticity (aging plasticity including aging reversal). According to this model, youth and aging are plastic and require constant maintenance, and, respectively, engage a host of endogenous rejuvenating (rejuvenins) and gero-inducing [geriatrin] factors.

Repair, regeneration and rejuvenation require un-entangling pluripotency from senescence.

There is a notion that pluripotency and senescence, represent two extremes of life of cells. Pluripotent cells display epigenetic youth, unlimited proliferative capacity and pluripotent differentiating potential whereas cells that reach the Hayflick limit, transit to senescence, undergo permanent inhibition of cell replication and create an aging tissue landscape. However, pluripotency and senescence appear to be intimately linked and are jointly generated in many different contexts such as during embryogenesis or formation of tissue spheroids, in stem cell niches, cancer, or by induction of a pluripotent state (induced pluripotency).

CircadiOmic medicine and aging.

The earth displays daily, seasonal and annual environmental cycles that have led to evolutionarily adapted ultradian, circadian and infradian rhythmicities in the entire biosphere. All biological organisms must adapt to these cycles that synchronize the function of their circadiome. The objective of this review is to discuss the latest knowledge regarding the role of circadiomics in health and aging.

Hydrogen sulfide facilitates reprogramming and trans-differentiation in 3D dermal fibroblast.

The efficiency of cell reprogramming in two-dimensional (2D) cultures is limited. Given that cellular stemness is intimately related to microenvironmental changes, 3D cell cultures have the potential of overcoming this limited capacity by allowing cells to self-organize by aggregation. In 3D space, cells interact more efficiently, modify their cellular topology, gene expression, signaling, and metabolism.

From genoprotection to rejuvenation.

Aging results from aberrations in signaling mechanisms and decline in biologic activities and cellular functions. Anti-aging strategies include a number of dietary, genetic, and pharmacological interventions that converge on a core network of nutrient sensors including AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), the insulin/insulin-like IIGF) growth factor signaling pathway (IIS), sirtuins, NFkB, and FOXO. Aging can be delayed and life-span and health-span can be extended by calorie and dietary restrictions, administration of NAM, NMN, NR, NAD+, and by antioxidants including hydrogen sulfide.

Signaling pathways and effectors of aging.

Aging leads to and is associated with aberrant function of multiple signaling pathways and a host of factors that maintain cellular health. Under normal conditions, the prolongevity, 5' AMP-activated protein kinase (AMPK), is dedicated to the homeostasis of metabolism and autophagy for removal of damaged cellular compartments and molecules. A host of sirtuin family of molecules, that extend life-span, regulate metabolism and repair DNA damage, and possess either mono-ADP-ribosyltransferase, or deacylase activity.

Cell-centric hypotheses of aging.

Aging in mammals results in numerous age related pathologies such as diabetes, and Alzheimer's disease which ultimately lead to organ failure and the demise of the organism. Numerous cell-centric hypotheses have attributed the disorders of aging to lie downstream to age dependent cellular damage to biologic signaling pathways, bio-informational molecules, telomeres, organelles, and stem cells. Here, we review these cell-centric causes of aging that range from the disposable soma theory, to somatic mutation theory, and free radical theory, to theories that ascribe aging to DNA damage and methylation (DNAaging and DNA superaging), impairment of autophagy (GarbAging), telomeric attrition, senescence, immunoscencence and inflammaging.

3-Mercaptopyruvate sulfurtransferase disruption in dermal fibroblasts facilitates adipogenic trans-differentiation.

Transitioning from a differentiated state to a higher-order of plasticity, by partial rather than full reactivation of pluripotency genes, might be a better approach in regenerative medicine. Hydrogen sulfide plays a crucial role in the maintenance and differentiation of mesenchymal stem cells (MSC) that have the potential to differentiate to a diverse group of mesenchymally derived cells. It was shown that these cells show a heavy reliance on cystathionine-β-synthase (CBS)-derived hydrogen sulfide (HS) during differentiation.

Replicative senescence is distinguishable from DNA damage-induced senescence by increased methylation of promoter of rDNA and reduced expression of rRNA.

Human fibroblasts become senescent after a limited number of replications or by diverse stresses, such as DNA damage. However, replicative and damage induced senescence are indistinguishable in respect to proliferation cessation and expression of senescence markers, senescence-associated β-galactosidase, p16 and p21. Here, we show that senescence types can be distinguished by reduced levels of 18S, 5.

Replicative Senescence in Human Fibroblasts Is Delayed by Hydrogen Sulfide in a NAMPT/SIRT1 Dependent Manner.

Recent evidence suggests that hydrogen sulfide (H2S) has cytoprotective and anti-aging effects. However, the mechanisms for such properties are not fully understood. Here, we show that the expression of the main H2S producing enzyme, CBS, and production of H2S are coordinately diminished in replicative senescent adult human dermal fibroblasts.

Nature creates, adapts, protects and sustains life using hydrogen sulfide.

Life emerged on Earth in an anaerobic environment, bathed in noxious gases. Among these gases, the role of hydrogen sulfide is significant since this gas, was required as a building block of life, contributed to abiogenic generation of organic compounds that gave rise to life and drove adaptations of life throughout its entire evolutionary path. During evolution, hydrogen sulfide contributed to sustaining life in face of harsh environmental conditions.

Homocysteine in Chronic Kidney Disease.

Hyperhomocysteinemia occurs in chronic- and end-stage kidney disease at the time when dialysis or transplant becomes indispensable for survival. Excessive accumulation of homocysteine (Hcy) aggravates conditions associated with imbalanced homeostasis and cellular redox thereby resulting in severe oxidative stress leading to oxidation of reduced free and protein-bound thiols. Thiol modifications such as N-homocysteinylation, sulfination, cysteinylation, glutathionylation, and sulfhydration control cellular responses that direct complex metabolic pathways.

Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S-Nampt.

Recently, we reported that cancer cells that recover from a potentially lethal damage gain new phenotypic features comprised of mitochondrial structural remodeling associated with increased glycolytic dependency and drug resistance. Here, we demonstrate that a subset of cancer cells, upon recovery from a potentially lethal damage, undergo dedifferentiation and express genes, which are characteristic of undifferentiated stem cells. While these cells are competent in maintaining differentiated progeny of tumor, they also exhibit transdifferentiation potential.

A H2S-Nampt dependent energetic circuit is critical to survival and cytoprotection from damage in cancer cells.

We recently demonstrated that cancer cells that recover from damage exhibit increased aerobic glycolysis, however, the molecular mechanism by which cancer cells survive the damage and show increased aerobic glycolysis remains unknown. Here, we demonstrate that diverse cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation, and develop tolerance to damage associated with increased production of hydrogen sulfide (H2S) which drives up-regulation of nicotinamide phosphoribosyltransferase (Nampt). Consistent with existence of a H2S-Nampt energetic circuit, in damage recovered cancer cells, H2S, Nampt and ATP production exhibit a significant correlation.

Cancer cells recovering from damage exhibit mitochondrial restructuring and increased aerobic glycolysis.

Instead of relying on mitochondrial oxidative phosphorylation, most cancer cells rely heavily on aerobic glycolysis, a phenomenon termed as "the Warburg effect". We considered that this effect is a direct consequence of damage which persists in cancer cells that recover from damage. To this end, we studied glycolysis and rate of cell proliferation in cancer cells that recovered from severe damage.

Isolation, characterization, and function of EBAF/LEFTY B: role in infertility.

Human endometrium exhibits cyclic stromal and glandular remodeling in preparation of embryo implantation. We identified EBAF/LEFTY B as a soluble cytokine of the TGF-β superfamily that is expressed at a low level in human endometrium during the receptivity period, while it is maximally expressed during perimenstrual and menstrual phases. Transfection of cells with EBAF/LEFTY B resulted in expression of a 42 kD protein that was proteolytically processed to release two polypeptides of 34 and 28 kD.

LEFTY, a member of the transforming growth factor-beta superfamily, inhibits uterine stromal cell differentiation: a novel autocrine role.

LEFTY is expressed in normal endometrium in cells that decidualize. To understand the importance of this expression, we have studied the effect of LEFTY on decidualization in vitro and in vivo. Exposure of human uterine fibroblast (HuF) cells to recombinant LEFTY blocked the induction of the decidual differentiation-specific marker genes, IGFBP1 (IGF-binding protein 1) and PRL (prolactin) in response to medroxyprogesterone acetate, estradiol, and prostaglandin E2.

Lefty peptides, derived by MMP2 cleavage, act as a new class of gelatinase A inhibitor.

MMPs are zinc-dependent endopeptidases that are involved in proteolysis of extracellular matrix in both physiological and pathological processes including cancer. MMPs are involved at all stages of tumor progression, including tumor growth, angiogenesis, and metastasis. We recently showed that overexpression of Lefty in cancer cells restrains tumor growth.

The regulated cell surface zymogen activation of the proprotein convertase PC5A directs the processing of its secretory substrates.

The proprotein convertases are synthesized as zymogens that acquire activity upon autocatalytic removal of their NH(2)-terminal prosegment. Based on the convertase furin, to fold properly and gain activity, the convertases PC5A, PACE4, and PC7 are presumed to undergo two sequential prosegment cleavages in the endoplasmic reticulum and then in the trans-Golgi network. However, biochemical and immunocytochemical experiments revealed that mouse PC5A is complexed to its prosegment at the plasma membrane.

Lefty at the crossroads of "stemness" and differentiative events.

Stem cells are functionally defined by their ability to self-renew and generate a progeny capable of creation or reconstitution of various tissues. Microarray analysis has shown a member of the transforming growth factor (TGF)-beta superfamily, Lefty, to be the single most abundant inhibitor in stem cells and in maternal decidua that supports embryo implantation. Lefty is regulated by pathways such as Smad (Sma and Mad [mothers against decapentaplegic]) and WNT (wingless-type) and by the transcriptional factor Oct3/4 (octamer-binding transcription factor 3/4), which support "stemness.

Tet responsive and adenovirus based constructs for regulated in vivo expression of Lefty.

Regulated expression of Lefty/Ebaf during embryogenesis is required for development of body asymmetry. A tight regulation of Lefty also contributes to the menstrual tissue shedding in humans. In order to replicate this regulated expression, we have developed a tet-on system and an adenovirus driven model.

Decidual differentiation of stromal cells promotes Proprotein Convertase 5/6 expression and lefty processing.

Lefty/Ebaf polypeptides, novel members of the TGF-beta superfamily, are involved in endometrial differentiation and embryo implantation. Recently, we showed that, during undisturbed estrous cycle, lefty is present in mouse uterine horn primarily in a precursor form. Here, we show that decidual differentiation of endometrial stroma leads to increased lefty (approximately 3.

Modeling gene expression in the mouse uterine horn by in vivo adenovirus-mediated gene delivery.

Endometrium is a unique tissue that is prepared for implantation of blastocyst during each menstrual cycle by expression of genes during a defined period of endometrial receptivity. Induction of gene over-expression in endometrium allows gaining insight on the role that genes play in endometrial function. Here, we show that induction of a state of gene over-expression in endometrium is feasible by in vivo gene delivery by transduction with adenovirus.

In vivo gene transfer of lefty leads to implantation failure in mice.

Background: Endometrium is a unique tissue that is prepared for implantation of blastocyst during each menstrual cycle. In humans, if implantation does not occur or fails, endometrium is shed.

Methods And Results: We identified ebaf/lefty, as a key cytokine, highly expressed in human endometrium during the non-receptive phase of tissue remodelling.