From Nuclear DNA Damage to Inflammatory Immune Aging via Cellular Senescence

Today I'll point out an open access paper in which the authors discuss some aspects of DNA damage with a particular focus on age-related inflammation and immune system dysfunction. Cells are fluid, dynamic landscapes of molecular machinery, near every component constantly damaged by inappropriate chemical reactions, but also constantly repaired and replaced. Little is static or lasting. The greatest, most intricate, and effective repair mechanisms are those that attend nuclear DNA, the blueprints for proteins and cellular operations that reside in the cell nucleus. One of the characteristics of aging is that despite the panoply of repair efforts, cells accumulate random nuclear DNA damage. Since the research community can't yet stop this from happening, there is considerable difficulty in separating out and quantifying this one particular contribution to the broader aging process. Certainly we can talk about cancer risk, and we can talk about rising numbers of cells becoming senescent in response to DNA damage, and researchers can disable DNA repair to observe the shortened life spans that result from such a fundamental breakage in cellular operation, but beyond that it becomes increasingly challenging to quantify effects within the scope of normal degenerative aging. If nuclear DNA damage was removed, such as via the somewhat distant molecular nanomachinery of chromallocytes, programmable nanorobots moving from cell to cell to fix each breakage, then aside from the elimination of cancer, would it have any other measurable effect on health and longevity? This is an unanswerable question at the present time.

Still, it will not remain unanswerable, and even today convincing and well-anchored arguments can be made either way, for and against the significance of nuclear DNA damage in aging. Interestingly, many of those on the side of nuclear DNA damage as being important in aging beyond cancer risk tend to pull senescent cells into the picture they paint. Senescent cells in turn produce inflammation, and chronic inflammation and related aspects of immune system decline are a big part of the broader progression of aging. This may well be more a sign of the times, a measure of the increasing interest in the research community directed towards the role of cellular senescence in aging, rather than something that arises organically. Certainly, much more funding is moving into efforts to treat aging by removal of senescent cells these days than was the case even a decade ago. The lines can be drawn, however, the connections made, but again it is hard to put numbers to these things without a way to remove nuclear DNA damage in isolation, carried out without influencing any other process relevant to degenerative aging.

From a long-term perspective, nuclear DNA damage is a thorny problem. It will be one of the hardest forms of damage to repair via rejuvenation biotechnology; the only one that springs to mind as likely being even more difficult is the matter of damaged nuclear pore proteins in long-lived cells, single molecules that might be as old as you are, doing the same job for an entire human life span. The only plausible methods of repairing stochastic nuclear DNA damage look to be the aforementioned advanced molecular nanotechnology, something that lies some decades in the future, or major advances in gene therapy, to the point at which it could be cost-effective and safe to scan and conditionally alter the majority of genes in the majority of cells all at once. When you stop to think about what would be required, it isn't clear that there is in fact much difference between the two items I mentioned there. Given this, it seems very plausible that in the decades ahead there will be many partially rejuvenated, active, healthy people at advanced ages walking around, all bearing very high levels of nuclear DNA damage, but protected from the consequent cancer incidence by highly effective next generation therapies. We shall see how it goes, but it certainly beats the present alternative of certain frailty and death.

DNA Damage: From Chronic Inflammation to Age-Related Deterioration

To withstand the hazards of existence, multicellular organisms need to preserve their bodily functions for long periods of time and protect themselves against pathogens. Taking the cell as a point of reference, the maintenance is directed inwards to counteract macromolecular damage. This often involves restoring injured nucleic acids back to their native form or replenishing proteins and lipids once damaged by harmful byproducts of metabolism. Further, cellular defense mechanisms, such as the innate immune responses are mainly directed outwards to protect the organism against irritants, pathogens, or injured cells. Since the problem of damage or the invasion of cells by pathogens has existed nearly ab initio, maintenance and defense must have arisen early during evolution. Indeed, even simple unicellular organisms such as bacteria possess multiple caretaking systems.

Remarkably, some prokaryotes employ a structurally distinct family of nucleases with a dual function e.g., in DNA repair and antiviral immunity. Similar to bacteria, mammals provide ample evidence that mechanisms of DNA repair and immunity have evolved together. For example, non-homologous end-joining is involved in the development of lymphocytes in resolving recombination intermediates i.e., DNA strand breaks (DSBs) that occur during V(D)J recombination. Likewise, "programmed" DNA lesions followed by error-prone DNA repair dramatically increase antibody diversity by triggering somatic hypermutation of immunoglobulin variable genes. Nonetheless, the evolutionary transition from one-celled microbes to more complex living systems has pushed for drastic changes in maintenance and defense strategies. In mammals, a single fertilized egg rapidly divides into several trillions of cells grouped into specialized tissues with marked differences in terms of developmental origin, regenerative capacity and ability to cope with damage. Moreover, tissues, organs and organ systems team up to perform specific tasks such as the body's first line of defense against bacteria or viruses. This inherent complexity arising from manifold levels of organization within multicellular life forms requires that genome maintenance, the DNA damage response (DDR) and defense strategies are tightly linked and highly coordinated processes.

Recent evidence points to reciprocal interactions between DNA repair, DNA damage responses and aspects of immunity; both self-maintenance and defense responses share a battery of common players and signaling pathways aimed at safeguarding our bodily functions over time. In the short-term, this functional interplay would allow injured cells to restore damaged DNA templates or communicate their compromised state to the microenvironment. In the long-term, however, it may result in the (premature) onset of age-related degeneration, including cancer. Until recently, there would have been few examples to link DNA damage and inflammation to health and disease. However, recent findings allow us to consider several instances where innate immune responses driven by intrinsic genome instability or chronic exposure to exogenous genotoxins is causal to age-related degeneration, metabolic abnormalities and cancer. Indeed, chronic inflammation is thought to generate an excess of reactive oxygen and nitrogen species (ROS, RNS) triggering DNA damage and malignancy. In support, chronic inflammation in the colon or the gastric cardia of mice is functionally linked to the formation of DNA lesions and the induction of the DDR, as well as with cancer induction.

Cellular senescence is a term used to describe cells that cease to divide in culture and has been one of the first paradigms to link DNA damage and immunity to disease. Cellular senescence is often fueled by nuclear DNA damage followed by chronic DDR activation; telomere shortening, mitogenic oncogenes, or intrinsic DNA damage can lead to different types of senescence limiting the replicative lifespan of cells. Persistent DNA damage and DDR signaling triggers senescent cells to secrete immunomodulatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). SASP factors range from inflammatory and immune-modulatory cytokines to chemokines as well as growth factors, shed cell surface molecules, survival factors and extracellular matrix remodeling enzymes. Together, they impinge on cell-fate decisions in neighboring cells or the tissue microenvironment. As DNA damage accumulates with age, persistent DDR-mediated release of SASP factors could be associated with degenerative changes that manifest with old age; in support, several SASP factors are considered amongst the most reliable biomarkers for age-related diseases.

Nevertheless, any direct evidence linking DNA damage to chronic inflammation stems from recent findings in progeroid (accelerated aging) syndromes and accompanying mouse models that carry inborn DNA repair defects. Patients with Werner syndrome (WS, associated with mutations in the RecQ DNA helicase) manifest with features of systemic chronic inflammation. Eventually, a universal theme arises from these recent findings; it is neither DNA damage nor senescence or cancer per se but persistent DDR that triggers the repertoire of innate immune responses. Thus, any events that could potentially activate DDR could trigger the activation of innate immune responses in the absence of DNA damage; similarly suppressing DDR signaling in the presence of tolerable DNA damage levels could alleviate some of the pathological features associated with DNA damage-driven inflammation.

DNA damage-driven inflammation can be both beneficial and detrimental for organismal survival. To understand this controversy, it may be helpful to consider that such responses have been selected for by having their early benefits outweigh their late costs during evolution. Early in life, priorities in mammals are shifted toward development, growth, and reproductive fitness. As cells divide, gain volume or differentiate, tissues rely on maintenance and defense mechanisms to efficiently detect and remove damaged cells. In doing so, specific cell types may activate immune responses to fine tune cell-fate decisions at the organismal level; for instance, DNA damage in germ cells induces an innate immune response in worms that promotes endurance of somatic tissues to allow delay of progeny production when germ cells are hit by DNA damage. Once reproductive maturity has been reached, the competitive advantage to signal the presence of damaged cells (in youth) is gradually deteriorating. Despite the efficiency of DNA repair mechanisms, some DNA damage is left unrepaired leading to the gradual accumulation of DNA lesions in cells. In turn, the slow but steady buildup of damaged cells within tissues is expected to intensify DDR responses over time. Likewise, the DDR-mediated pro-inflammatory signals may further alarm the neighboring cells and tissues for the presence of cells with compromised genome integrity. The latter triggers a vicious cycle of persistent DDR and pro-inflammatory signals leading to chronic inflammation, tissue malfunction and degeneration with old age; in DNA repair-deficient patients, the rapid accumulation of DNA damage (in view of the DNA repair defect) would trigger the untimely activation of DDR signaling leading to the early manifestation of age-related pathology that is associated with chronic inflammation.