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The central role of chromatin maintenance in aging

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The central role of chromatin maintenance in aging


Abstract

Epigenetic regulation of chromatin and the DNA damage response are now well appreciated key players in human aging. What contributions chromatin and DAN repair make to aging, whether they are causal, and how these relate to other aging pathways, however, is unclear. Novel insights into the aging-related molecular mechanisms that link chromatin and DNA damage repair have recently been gained by studying models of both premature and physiological aging. Here we discuss these findings and we propose a broad framework for the role of chromatin in aging to reconcile apparently contradicting evidence obtained in various experimental systems.

Introduction

Cells are continuously exposed to a wide variety of physical and chemical stresses such as oxidation, radiation and heavy metals, which cause damage to cellular proteins, lipids and DNA. Organisms have evolved multiple protective mechanisms to counteract these endogenous and exogenous damages. Nevertheless, the effectiveness of these protective pathways seems to decline with age. As such, aging can be defined as the decrease in the probability of successful repair of cellular damage.

One of the major sources of cellular insults is damage to DNA. To counteract detrimental DNA damage, cells are endowed with a complex network of DNA damage response (DDR) proteins which are capable of detecting DNA damage, and then triggering and amplifying a signaling cascade, which ultimately leads to either cell-cycle arrest and DNA repair, or to apoptotic cell death to eliminate permanently damaged cells [1]. The importance of the DDR in maintaining genomic integrity and limiting the effects of aging is highlighted by premature aging phenotype of mice that lack key DNA repair factors [2]. More tellingly, almost all genetic conditions that lead to premature aging in humans have been mapped to genes belonging to the DDR [3]. Mutations in the Werner DNA helicase, which is required for DNA replication and at telomeres, lead to Werner syndrome and the components of the nucleotide excision repair (NER) XPC, ERCC6, ERCC8 and the ERCC1/XPF complex involved in inter-strand DNA crosslink repair are mutated in Cockayne Syndrome and in Trichothiodystrophy (TTD), two prominent premature aging disorders [4]. These findings suggest a prominent, and causal, role for DNA damage responses in aging.

The DDR, like all major nuclear processes such as DNA replication and transcription, operates in the context of the chromatin fiber [5,6]. Chromatin is made up of nucleosomes, repetitive units of 146bp of DNA tightly wrapped around an octameric core of histone proteins (H2A, H2B, H3 and H4). Nucleosomes are further packaged into higher order structures by the action of architectural chromatin proteins such as histone H1 and heterochromatin protein HP1. Based on cytological criteria, chromatin is classified into euchromatin, which is loosely packed and generally transcriptionally active, and into heterochromatin, which is more compacted and generally represents a transcriptionally repressive environment. Nucleosomal histones are modified by complex patterns of post-translational modifications (PTM) such as acetylation, methylation and ubiquitination which appear to dictate the dynamic recruitment of non-histone proteins to chromatin and regulate its function [7]. Furthermore, chromatin structure and function is also determined by the methylation status of DNA itself and by a large number of ATP-dependent remodeling factors. Both the level of chromatin compaction, and hence the accessibility of DNA, and the recruitment of chromatin-associated factors determine the outcome of transcription, DNA replication and DNA damage repair. All these modifications to chromatin structure, and thus its informational content, are inherited through several cycles of cell division and as such represent an epigenetic memory [8].

Chromatin defects in aging

Chromatin defects are associated with aging. The first hints pointing to a possible link between chromatin maintenance and aging came from studies in the yeast S. cerevesiae, where the NADH-dependent Sir2 histone deacetylase Sir2 was found to be important for establishing heterochromatin at telomeres, at ribosomal DNA (rDNA), and at HMR and HMR loci, which encode factors needed for yeast mating type switching [9-14]. Upon prolonged growth, equated to aging in yeast, repetitive rDNA tends to hyper-recombine and form extrachromosomal rDNA circles (ERC), indicative of increased chromatin fragility [15]. Formation of heterochromatin at rDNA sites by overexpression of Sir2 reduces this hyper-recombination and prolongs lifespan, suggesting a contribution of chromatin structure to aging [16]. Further experiments in worms and flies demonstrated a similar role in lifespan extension for Sirt1, the closest orthologue of yeast Sir2 in these organisms [17,18]. Nevertheless, the role of Sirt1 in increased longevity in higher eukaryotes might not just involve heterochromatin maintenance, since in this case the molecular mechanism does not seem to involve ERC stabilization [19]. Furthermore, the analysis is complicated by the fact that in mammals SIRT1 deacetylates a wide variety of non-histone, aging-related transcription factors such as p53, HSF1 and members of the FOXO transcription factors family [20-22]. Identification of the mechanisms of action of SIRT1 in higher organisms will be key to clarifying its role in the aging process.

There are several other clear indications for a role of chromatin and its maintenance in aging. A hallmark of cellular aging is the appearance of characteristic changes in the epigenetic make-up of the genome. Epigenetic changes associated with aging in mammalian cells include loss of DNA methylation at repetitive DNA sequences [23-25], which are generally heterochromatinized, and an increase in DNA methylation at CpG islands in the promoters of specific genes [26,27]. Cells from aged individuals and patients with the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) are also characterized by loss of heterochromatin, by loss of key architectural chromatin proteins such as HP1 and the histone mehtyltransferase EZH2, and, importantly, by alterations in the levels of heterochromatin-associated histone PTM including H3K9me3 and H3K27me3 [28-31]. Interestingly, both prematurely and normally aged cells exhibit dramatically increased levels of unrepaired DNA damage [30,32].

In addition to epigenetic and structural chromatin defects, there are indications that aging in mammals is accompanied by stochastic deregulation of gene expression. Transcriptional noise at the single cell level increases with age in the mouse heart, most likely as a consequence of oxidative DNA damage [33]. Furthermore, in mammalian cells oxidative DNA damage also seems to relocalize SIRT1 from otherwise transcriptionally repressed genes to sites of DNA damage [34]. This has led to the speculation that, through unknown mechanisms, aging disrupts the epigenetic organization of heterochromatin both at a global and at a gene-specific level, thus leading to elevation of stochastic transcriptional noise and to the disruption of transcriptional programs necessary for proper cell homeostasis [35]. In contrast to this model of stochastically occurring defects in gene expression programs, the aging process seems to also induce a specific transcriptional response, which dampens the somatotrophic IGF-1 axis and helps protecting cells from DNA damage and stress [36].

The study of chromatin in aging also points to a key influence of aberrant chromatin structure on aging-related defects in DNA repair. Impairment of SIRT1 leads to defective DNA damage repair in mammalian cells [34] and a knock-out mouse model for SIRT6 shows signs of premature aging and has defects in the base excision repair pathway [37]. The exact molecular basis for these phenotypes is not clear yet. One possibility is that SIRT6 affects genomic stability by regulating the levels of H3K56Ac [38,39], a PTM important for chromatin assembly and DNA damage tolerance in yeast [40,41].

A molecular mechanism for aging-associated chromatin defects

The molecular mechanisms leading to chromatin defects in aging are largely unknown. Recent analysis of chromatin defects in the premature aging disease HGPS have given some of the first insights into how chromatin ages [42]. HGPS is an extremely rare genetic disease caused by a de novo point mutation in the lamin A (LMNA) gene, a major structural component of the nuclear envelope [43].The pathogenic mutation leads to the production of an internally truncated form of lamin A, referred to as progerin. This protein acts in a dominant-negative gain of function fashion causing the diverse and pronounced chromatin defects. Analysis of the molecular mechanisms involved in bringing about chromatin defects in HGPS and old cells uncovered the NURD complex as a key player in aging [42]. NURD is a ubiquitous chromatin remodeling complex which contains the histone deacetylases HDAC1 and HDAC2 and the ATPases CHD3 and CHD4 as catalytic subunits. NURD has been implicated in transcriptional repression at specific promoters and more recently has also been shown to associate with pericentromeric heterochromatin [44,45]. The protein levels and the activity of several NURD components including HDAC1 and the histone chaperones RBBP4/, are reduced in HGPS cells and normally aged cells. A direct role for NURD loss in aging-associated chromatin defects is indicated by the finding that knock-down of NURD members in normal cells recapitulates aging-related chromatin defects including heterochromatin loss and increased DNA damage [42]. NURD is known to be involved in a variety of chromatin functions and its loss may explain the broad spectrum of chromatin defects seen in aged cells [42]. https://www.aging-us.com/issue/v1i12


Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on various biomedical themes, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1. He also was the last author for a clinical phase I/II trial article. 
After authoring seven papers during a brief yet productive senior research fellowship in the El-Deiry Cancer Research Lab at the University of Pennsylvania, Dr. Blagosklonny returned to NCI to work with Tito Fojo. Together, they published 26 papers. Moreover, Dr. Blagosklonny published many of experimental research papers and theoretical papers as sole author. The abovementioned sole-author articles discussed two crucial topics. The first of these discussed selectively killing cancer cells with deregulated cell cycle or drug resistance via verifying their resistance. The outcomes and underlying notion were so revolutionary that they were incorrectly cited by other scientists as “reversal of resistance,” even though the publication was titled, “Exploiting of drug resistance instead of its reversal.” One big supporter of this concept was the world-famous scientist Arthur Pardee, with whom Dr. Blagosklonny co-authored a joint publication in 2001.
The second theme throughout Dr. Blagosklonny’s sole-author articles is a research method to develop knowledge by bringing several facts together from seemingly irrelevant areas. This results in new notions with testable forecasts, which in turn can be “tested” via analyzing the literature further. Likewise, the concept was co-authored by Arthur Pardee in a 2002 article in Nature. The first success of the new research methodology was the description of the feedback regulation of p53, as confirmed by the discovery of mdm2/p53 loop; and the explanation why mutant p53 is always overexpressed, published in 1997. The most important result revealed by Dr. Blagosklonny’s research methodology is the hyperfunction (or quasi-programmed) theory of aging and the revelation of rapamycin as an exclusively well-tolerated anti-aging drug, published in 2006. As mentioned in Scientific American, Michael Hall, who discovered mTOR in 1991, gives Dr. Blagosklonny credit for “connecting dots that others can’t even see.”
In 2002, Dr. Blagosklonny became associate professor of medicine at New York Medical College. He agreed to accept responsibilities as a senior scientist at Ordway Research Institute in Albany, New York, in 2005, before receiving another position at Roswell Park Cancer Institute as professor of oncology in 2009.
Since coming to Roswell Park Comprehensive Cancer Center in 2009, Dr. Blagosklonny has studied the prevention of cancer (an age-related disease) via stopping organism aging - in other words, “preventing cancer via staying young.” His laboratory closely worked together with Andrei Gudkov’s and conducted research on the suppression of cellular senescence, namely suppression of cellular conversion from healthy quiescence to permanent senescence. This led to the discovery of additional anti-aging medicines beyond rapamycin. The cell culture studies were complemented by studies in mice, including several models like normal and aging mice, p53-deficient mice, and mice on a high-fat diet.
Dr. Blagosklonny has also published extensively on the stoppage of cellular senescence via rapamycin and other mTOR inhibitors, life extension and cancer stoppage in mice, and combinations of anti-aging medicines to be taken by humans. A rapamycin-based combination of seven clinically available medications has been named the “Koschei Formula” and is now used for the treatment of aging in patients at the Alan Green Clinic in Little Neck, New York. 

When general population speak of contemporary medicine, accuracy plays one of the most crucial roles and people’s lives are literally dependent on it. Hence, any researches related to medicine are required to meet the top standards. The challenge today is that any recommendations of researches can be published online and used as a reference without being properly verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this problem and attempted to generate an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been established back in 2010. The key principle of this journal is based on Altmetric scores that are used as a quality indicator. That assists both readers and authors to validate publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a full publications list with respective scores higher than 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the necessary assistance to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was published back in 2018 by Oncotarget and written by diversified experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are aiming to understand the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Likewise, the paper about melanoma, was used for citations in different news articles 69 times. Besides that, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive useful scientific facts. Oncotarget is glad to have the ability to share with online customers this highly appreciated and top-quality information, that is trustworthy and reliable.

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