A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing

Abstract

It is estimated that 10–50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day. Repeated genomic integration of cfCh may have catastrophic consequences for the cell, such as DSBs, their faulty repair by nonhomologous end joining (NHEJ) followed by apoptosis with release of more cfCh which would integrate into genomes of surrounding cells. This can creates a vicious cycle of cfCh integration, DSBs, NHEJ, and more apoptosis, thereby providing a potential explanation as to why so many billions of cells die in the body on a daily basis. We also recount the recent observation that cfCh integration and the resulting DSBs activate inflammatory cytokines. This leads us to propose that concurrent DSBs and induction of inflammation occurring throughout life may be the underlying cause of ageing, degenerative disorders, and cancer. Finally, we discuss the prospect that agents that can inactivate/degrade cfCh may hold the key to making healthy ageing a realizable goal.

A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration

“…For example, cfChPs can readily enter into the healthy cells to damage their DNA, activate inflammatory cytokines and promote apoptosis via the mitochondrial pathway [13, 14]. Given that 1X10 9 -1X10 12 cells die in the body every day [56, 57], we have hypothesised that repeated and lifelong assault on healthy cells by cfChPs derived from the dying cells might be the underlying cause of ageing [15, 16]. In support of this hypothesis we show in this article that prolonged oral administration of R-Cu to ageing mice down-regulated multiple biological hallmarks of ageing and neurodegeneration.…”

“…In this context, we have reported that cell-free chromatin particles (cfChPs) that are released from the billions of cells that die in the body every day, and enter into the extracellular compartments of the body, can be readily internalised by healthy cells wherein they inflict dsDNA breaks, activate apoptotic pathways and induce inflammatory cytokines [13, 14]. This has led us to hypothesise that repeated lifelong assault on healthy cells by cfChPs may be the underlying cause of ageing [15, 16]. Our group has successfully isolated and characterised cfChPs from human serum, which upon EM examination revealed extensive size heterogeneity ranging between ∼10nm and ∼1000nm [13].…”

A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001)

“…It has been reported that cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body everyday can integrate into genomes of healthy cells to trigger dsDNA breaks, apoptosis and activation of inflammatory cytokines [5,6]. We have hypothesized that repeated genomic integration of cfCh particles occurring throughout life may be the underlying cause of ageing and degenerative disorders [7,8]. We have previously reported that toxicity of chemotherapy is largely not due to the direct effects of the drugs themselves; rather it is mainly due to DNA damage, apoptosis and hyper-inflammation triggered by cell-free chromatin particles that are released because of drug induced host cell death [9].…”

A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration in mice

“…In this context, we have reported that cell-free chromatin particles (cfChPs) that are released from the billions of cells that die in the body every day, and enter into the extracellular compartments of the body, can be readily internalised by healthy cells wherein they inflict dsDNA breaks, activate apoptotic pathways and induce inflammatory cytokines 13 , 14 . This has led us to hypothesise that repeated lifelong assault on healthy cells by cfChPs may be the underlying cause of ageing 15 , 16 . Our group has successfully isolated and characterised cfChPs from human serum, which upon EM examination revealed extensive size heterogeneity ranging between ~ 10 and ~ 1000 nm 13 .…”