Reversing hallmarks of rapid aging by silencing a cellular alarm system
Photo credit: Eitan Moses
One of the difficulties creationists have with presenting the immune system as evidence of intelligent design is explaining why something supposedly designed to protect us so often contributes to our illnesses. A defence system that can turn the body's own damaged DNA into a trigger for further damage is hardly an obvious example of competent, benevolent engineering. It is, however, entirely understandable as a product of evolution: a collection of mechanisms favoured for their benefits, constrained by their history, and carrying costs that natural selection has never eliminated.
Research from the Hebrew University of Jerusalem provides a revealing example. In a paper published in Genes & Development, Marva Bergman and colleagues investigated how a DNA-sensing protein called cGAS contributes to disorders involving defective DNA repair; the body's response to genetic damage can itself become an important source of harm.
The underlying problem is straightforward. DNA appearing in the fluid surrounding a cell's nucleus can be a warning of infection. cGAS helps detect it and activates an inflammatory defence response. But the DNA need not belong to a virus: damaged cells can expose their own DNA to the same sensor. Consequently, an alarm that normally helps protect against infection can sustain inflammation even when there is no invading organism to fight. The response then risks damaging the very tissues it ordinarily helps defend.
The researchers modelled two human DNA-repair disorders, ataxia-telangiectasia and Bloom syndrome, in turquoise killifish, Nothobranchius furzeri. In the ataxia-telangiectasia model, disrupting the gene for cGAS partially alleviated reproductive defects, cellular senescence in the liver, and inflammation in the cerebellum. Several measures of genome instability also improved, consistent with cGAS having additional effects inside the nucleus, beyond its familiar inflammatory role.
There was, however, a crucial complication: losing cGAS in fish without the underlying repair defect made pathology and genome instability worse. This was therefore no demonstration that the immune system contains a universally dispensable component, nor a discovery that switching off one gene reverses normal ageing. The same protein could be beneficial or harmful depending on the biological circumstances.
That is precisely where the evolutionary explanation becomes useful. A sensor that responds to DNA in an unusual location offers a broadly effective means of detecting danger, but that signal does not identify the DNA's origin with certainty. Such a system needs safeguards and regulation, and its usefulness does not guarantee that those safeguards will work under every condition. Natural selection can preserve a mechanism whose overall benefits outweigh its costs; it cannot anticipate every future mutation or guarantee freedom from disease.
The study did not test the evolutionary history of cGAS, but its findings illustrate the kind of context-dependent compromise evolution produces. For intelligent-design advocates, the awkward question is why an allegedly perfect designer would make protection and self-inflicted damage so intimately connected. For evolutionary biology, the useful question is how that connection works—and whether understanding it can help us reduce the harm.
This is just one example of how the human body is not a work of perfect design, but the product of sub-optimal compromises constrained by contingent history and lacking in foresight, where additional layers of complexity are not hallmarks of intelligent design that creationists like to imagine, but of the need for controls and compensations for problems created by earlier iterations of the evolutionary cycle. Many more are explained in my book, The Body Of Evidence: How The Human Body Refutes Intelligent Design
When protection becomes pathology. The immune system is essential to survival, but its destructive capabilities are not perfectly controlled. It can attack the body's own tissues, react to harmless substances, or cause extensive collateral damage while fighting a genuine infection. These are different routes to disease, rather than one universal immune-system malfunction.The paper in Genes & Development was accompanied by a press release from the Hebrew University of Jerusalem, made available via The American Friends of the Hebrew University.
Disease or condition How the immune system causes harm Type 1 diabetes An autoimmune response destroys insulin-producing beta cells in the pancreas. The resulting insulin deficiency disrupts blood-glucose regulation and usually requires lifelong insulin treatment. Genetic susceptibility and environmental factors contribute, but the initiating events are not fully understood. [NIDDK] Rheumatoid arthritis Immune activity sustains inflammation in the lining of joints. This can progressively damage cartilage and bone, producing pain, deformity and disability. The disease can also affect organs outside the joints. [NIAMS] Systemic lupus erythematosus — lupus The immune system reacts against the body's own components, causing inflammation and tissue damage. Depending on which tissues are affected, the consequences can include skin disease, joint pain and serious kidney or other organ damage. [NIAMS] Coeliac disease In susceptible people, eating gluten triggers an immune response that damages the lining of the small intestine. This reduces its ability to absorb nutrients. Coeliac disease is an autoimmune condition, rather than an ordinary food allergy. [NHS] Hay fever and other allergies The immune system responds to normally harmless substances, such as pollen or particular food proteins. The resulting reaction can cause itching, sneezing, swelling and other symptoms without providing a useful defence against infection. [NHS] Anaphylaxis A severe allergic reaction can rapidly compromise breathing and circulation. A food protein, medicine or insect sting can therefore trigger a defensive response whose consequences are life-threatening. [NHS] Gout Urate crystals accumulate in or around joints and provoke inflammation, causing intense pain and swelling. The inflammatory response to these deposits is an important source of suffering; no invading pathogen is required. [NIAMS] Sepsis A dysregulated response to infection causes life-threatening organ dysfunction. Inflammation, abnormal clotting and leaky blood vessels can impair tissue circulation. Immune suppression can also occur, so sepsis is more complicated than simply having an “overactive” immune system. [NIGMS]
Why evolution leaves these vulnerabilities
Immune defence involves competing demands: detecting danger without reacting to everything; destroying infected cells while sparing healthy tissue; and producing inflammation rapidly enough to contain infection, then switching it off before it causes excessive damage. The mechanisms that regulate these responses are effective enough to sustain life, but they are not infallible.
Natural selection acts on inherited variation through its effects on survival and reproduction. It has no foresight and cannot rebuild an organism from scratch. A protective mechanism can therefore persist despite harmful effects in particular circumstances. This does not mean that each immune-mediated disease is itself an adaptation, or that its precise evolutionary explanation is already known.
These conditions illustrate the limitations of an evolved defence system. Its complexity is compatible with accumulated modifications and imperfect regulation; complexity alone is no evidence of intelligent, benevolent design.
How the Immune System Rewrites Rapid Aging
Dialing down an overactive immune sensor can restore tissue health in severe genetic disorders and restore function across multiple biological systems, according to a new study by researchers at the Hebrew University of Jerusalem (HU).
The human immune system is finely tuned to detect and destroy viral threats, yet it can backfire. When fragments of the body’s own damaged DNA are mistaken for viral invaders, the result is a powerful, misplaced inflammatory response that harms the body it is meant to protect. For decades, scientists believed that the accumulation of unrepaired DNA was the primary cause of cellular decline. This study, published in Genes & Development, challenges that view.
The research team, led by HU researchers Dr. Marva Bergman, Prof. Itamar Harel, and Prof. Yehuda Tzfati of the Department of Genetics at the Alexander Silberman Institute of Life Science at HU, focused on rare DNA damage-repair (DDR) syndromes such as ataxia-telangiectasia (A-T) and Bloom syndrome. In these conditions, the machinery that normally repairs everyday DNA damage is impaired, leading to widespread genomic instability, neurodegeneration, cancer susceptibility, and premature aging.
Our results show that the damage isn’t acting alone. It’s the body’s response to that damage, an exaggerated, chronic inflammatory reaction, that drives much of the degeneration.
Professor Itmar Harel, co-senior Author
Department of Genetics
The Silberman Institute
The Hebrew University of Jerusalem
Jerusalem, Israel.
When DNA repair fails, fragments of DNA can leak into the cell’s cytosol, where they activate a molecular sensor known as cGAS. This pathway typically detects viral DNA, but it cannot reliably distinguish between foreign and self-derived fragments. The result is a sustained, sterile inflammatory response that damages tissues.
The researchers also uncovered a second, unexpected role for cGAS. Beyond triggering inflammation, it can enter the cell nucleus and directly interfere with DNA repair processes. This dual function makes it both a protector under normal conditions and a potent driver of damage when the system is overwhelmed.
To test whether moderating this response could alter disease progression, the team used a fast-aging vertebrate model that allows rapid evaluation of aging-related processes. When cGAS activity was reduced in this system, key disease features, including neuroinflammation, tissue degeneration, and loss of reproductive capacity, were substantially improved.
We weren’t just slowing decline, we saw broad restoration of tissue function. It suggests that the body can cope with more DNA damage than we assumed, if the inflammatory response is kept in check.
Dr Marva Bergman, lead author.
Department of Genetics
The Silberman Institute
The Hebrew University of Jerusalem
Jerusalem, Israel.
The implications for treatment are significant. Rather than attempting to repair every DNA lesion, therapies could focus on modulating how the body responds to damage. However, the researchers caution that cGAS also plays a critical role in antiviral defense, meaning that future therapies will need to selectively dampen harmful activity without compromising immunity.
Beyond rare genetic disorders, the findings may have broader relevance for age-related diseases, where chronic inflammation and genomic instability often coexist.
Importantly, the researchers note that reversing severe disease processes is different from slowing the intrinsic pace of aging. Still, by identifying how the body’s own alarm systems contribute to decline, this study opens a promising new direction for treating some of the most challenging degenerative conditions.
Researchers:
Marva Bergman, Uri Goshtchevsky, Tehila Atlan, Gwendoline Astre, Ryan Halabi, Hosniyah El Ayoubi, Eitan Moses, Aaron J.J. Lemus, Bérénice A. Benayoun, Yehuda Tzfati, Ido Ben-Ami, Itamar Harel
Institutions:
- Department of Genetics, the Silberman Institute, the Hebrew University of Jerusalem
- Department of Obstetrics & Gynecology, the Eisenberg R&D Authority, Shaare Zedek Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem
- Leonard Davis School of Gerontology, University of Southern California
- Molecular and Computational Biology Department, USC Dornsife College of Letters, Arts, and Sciences, Los Angeles
Publication:
For intelligent-design creationists, the difficulty is that the same molecular machinery can help protect the body in one context and contribute to its deterioration in another. In this study, removing cGAS alleviated several defects in fish with impaired DNA repair, yet caused problems in otherwise healthy fish. That is the sort of context-dependent compromise an evolutionary history can produce. Presenting it as the work of an omniscient, benevolent designer raises an awkward question: why should essential protection be so entangled with mechanisms of self-inflicted harm?
Invoking “The Fall” merely replaces a biological problem with a theological one. If an omniscient creator foresaw the consequences, then these vulnerabilities were no surprise. If that creator deliberately introduced them as punishment, the suffering becomes intentional. If they arose through some independent process, an omnipotent creator could presumably have prevented or corrected them. Blaming ancestral disobedience does nothing to explain why children should suffer inherited disorders, or why animals that made no moral choice should share the consequences. It leaves the creationist defending collective punishment and preventable suffering as expressions of perfect justice and love.
Then there is to unanswered question; did humans get their immune system at the original creation or did they get this faulty upgrade later, after 'The Fall'? In the former case the 'designer' knew 'The Fall' would happen and planned for it; in the latter case the ‘designer’ should have known exactly what was needed and made a better job of it, and any claim of omniscience has to be abandoned.
Nor does “The Fall” provide a scientific explanation. It supplies no testable account of how a DNA sensor acquired its particular functions, why its effects depend on the condition of the cell, or which intervention might reduce its harmful activity. Evolutionary biology requires no original perfection followed by supernatural deterioration. It provides a framework in which useful mechanisms can have limitations, inherited defects can disrupt regulation, and natural selection can preserve benefits without eliminating every cost.
The practical progress comes from investigating those mechanisms. Understanding how an immune response amplifies damage may eventually help researchers limit that damage while preserving necessary protection. The study offers no universal cure for ageing, but it does show why treating biological complexity as proof of intelligent design explains so little. Science advances by discovering how the system works—including how it fails—while “The Fall” leaves both the mechanism and the morality unexplained.
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