Abstract
This article presents the concept of Antagonistic Pathogenic Pleiotropy, in which an abnormality that causes a specific pathology can simultaneously reduce other morbidities through unrelated mechanisms, resulting in the pathology causing less morbidity or mortality than expected. The concept is illustrated by the case of essential thrombocythemia (ET). Patients with ET have substantially elevated platelets and are therefore expected to have increased thrombotic events leading to reduced life expectancy. However, patients with ET do not have reduced life expectancy. A possible explanation is that elevated platelets produce higher levels of platelet factor 4 (PF4), which has been found to reduce age-associated decline in immune and cognitive function in mice and has been suggested as a treatment for age-associated illness. The benefit of elevated PF4 is hypothesized to balance the increased morbidity from hematological causes. Searches for other indications where a well-defined pathology is not associated with concomitant reduction in overall mortality may be a route to identifying factors that could protect against, prevent, or treat chronic disease.
Introduction
Pleiotropy, the effect of a gene on more than one distinct phenotype, is widespread in biology. 1 Antagonistic pleiotropy is a model to explain the deleterious effects of gene variants or physiological processes in older people. Specifically, some alleles that provide selective advantage in young, reproductively active animals have effects that are deleterious in later life, when selection is weaker. 2 The concept of antagonistic pleiotropy is a prominent explanatory framework for the near-universality of aging among animals. 3 –5 A range of late-onset diseases are proposed to be the result of specific selection for mechanisms that increase fertility in humans. 5
Pleiotropy does not operate solely at a genetic and developmental level. Pleiotropic effects acting at the phenotypic level (e.g., the pleiotropic effects of growth factors on growth, metabolism, and aging 6,7 ) can point to modifiable processes that could be the target of therapeutic intervention. This article introduces the idea of antagonistic pathogenic pleiotropy (APaP), whereby a mechanism that has been identified primarily as causing pathology in one organ or system might simultaneously, as an unrelated effect, cause benefit in others through different mechanisms. There is unlikely to be a selection for either the pathology or the fortuitous positive “side effect”—they are the accidental consequence of the necessarily highly interconnected nature of physiology. 8 The net effect of the original pathogenic effect and its unrelated beneficial side effect is to offset the deleterious effect of the pathogenesis, and hence reduce morbidity or mortality. If the mechanism of the hypothesized beneficial effect can be identified, it could be a candidate for redirection into a therapeutic.
I illustrate this in detail with the example of the unexpectedly normal life expectancy of patients with essential thrombocythemia, where the concept may apply, before suggesting how searching for this effect in other indications may lead to therapeutic insights.
Essential Thrombocythemia and Platelet Factor 4
Elevated platelets (thrombocytosis) can be the result of a wide range of nonhematological processes, 9 but is also sometimes seen as an isolated phenomenon with no clear external cause, a condition known as essential thrombocythemia (ET). 10,11 ET can be driven by myeloid stem cell mutations, 12,13 or be of unexplained etiology, but in either case is managed by alkylating agents, hydroxycarbamide, or alpha-interferon. 14 –16 However, platelet load usually remains above normal, with a balance being struck by the clinician between the adverse effects of treatment versus the risk of elevated platelet count. 17,18
Blood clotting in patients with ET is dysregulated. Increased platelet load can lead to increased clotting, while increased absorption of von Willebrand factor onto platelets can paradoxically lead to subnormal clotting. 19 As a result, patients with ET are at increased risk of thrombohemorrhagic sequelae. 16,20 –23 Patients with thrombocytosis (elevated platelet counts) from any cause also have poorer outcomes of infections by pneumonia 24 and SARS-CoV-2, 25 among others. Despite this, life expectancy among patients with ET is not found to be substantially below that of matched controls. 26 A potential reason for this is that platelets could also reduce mortality from other causes. Recent work has suggested that the mechanism by which excess platelets could exert a beneficial effect is through their secretion of platelet factor 4 (PF4), which has been shown to have an antiaging effect in some systems.
Platelet factor 4 as an agent to slow cognitive and immune aging
Platelet factor 4 (PF4) (also known as CXCL4) is a chemokine made in megakaryocytes and stored in their progeny platelets that is released on platelet activation. 27 It has multiple roles in endothelial and immune biology. 28 PF4 levels are elevated in patients with ET even if their platelet counts are well controlled. 29
Heterochronic parabiosis experiments suggest that PF4 has rejuvenating or antiaging effects. Heterochronic parabiosis is the surgical manipulation of an animal such that an old animal shares circulation with a young one. 30 –32 Many specific factors in “young” blood have been suggested as the primary mediators of this effect. 33 –37 Recent experiments have suggested that “young” platelets, and specifically PF4, decrease inflammation in the hippocampus in aged mice, 38 and can lead to improved cognition 39,40 and neurogenesis 41 in older mice, which may be related to PF4 improving immune profiles and reducing “inflammaging.” 42,43 Exercise-activated platelets have been found to stimulate dentate gyrus neurogenesis, probably through PF4. 44 More widely, circulating PF4 is lower in older mice and humans than in younger ones, 38 suggesting that PF4 may have protective effects in humans as well as mice.
PF4 may also have an effect on cancer, although in these studies the conclusions are more mixed. PF4 has antiangiogenic properties and has been suggested as an angiostatic in cancer treatment. 45 –48 It may also modulate the environment of premetastatic epithelial tumors to retard tumor progression. 49 However, PF4 has also been associated with progression in lung cancer, 50,51 and platelet activation (which releases PF4 as well as other effectors) can suppress antitumour immune responses. 52,53 Whether elevated PF4 would reduce the overall burden of cancer morbidity and mortality is therefore not clear.
PF4 is also a marker and potential mediator of fibrosis in hepatic cirrhosis, 54,55 pulmonary arterial hypertension, 28 primary myelofibrosis, 56 and cardiac and vascular fibrosis 57 in humans and animal models. However, these may be local effects, as systemic PF4 substantially attenuates liver damage in a mouse model of liver damage. 58 Platelet granules from which PF4 is released also contain other profibrotic proteins, such as PDGF and TGF-β, so it is not clear in all cases whether PF4 is a cause or a marker for fibrosis. The effect of global PF4 elevation in ET on fibrosis remains to be explored.
Hypothesis: Antagonistic pathogenic pleiotropy in the PF4 system
I hypothesize that in human patients with ET, the elevated levels of PF4 that result from moderately elevated platelet levels cause modulation of immune status, and as a consequence reduce several morbidities of aging to a small extent, especially cognitive decline and inflammaging. This small reduction of morbidity is sufficient to balance the increased morbidity from dysregulation of hemostasis, resulting in a comparable lifespan in patients with ET to that of people without ET. The concept is summarised in the graphical abstract. This compensating beneficial effect of a pathogenic process is an example of APaP. If PF4 does have a morbidity-reducing effect, potentially through modulation of the immune system, then ET would be an example of APaP—a pathological elevation in platelets causing a concomitant increase in PF4, which has a balancing positive effect on longevity through mechanisms unrelated to the thrombotic sequelae of thrombocytosis.
Implications for management of essential thrombocythemia
This hypothesis has specific implications for the management of ET. If PF4 is balancing the increased mortality risk of ET’s hemostatic risks, then the incidence of comorbidities and the mortality of ET patients should be predictable at least in part from their PF4 levels, independent of their platelet counts. Comorbidities are easier to measure than lifetime mortality and could be studied alongside PF4 levels and whole blood counts. This would be complex, as the drugs used to treat ET themselves have systemic effects, not all benign, but could in principle be achieved. The contrast between ET and polycythemia vera, where platelets are also elevated and life expectancy is significantly reduced, 26 may be informative. If this prediction of borne out, then PF4 levels could be used to guide adjunct treatment of ET, for example with low-dose aspirin. 18
Discussion and Implications
More generally, APaP could suggest other interventions with beneficial effects in humans. Specifically, a search could identify conditions or diseases for which the underlying pathology suggests that patients should suffer increased morbidity or reduced life expectancy despite effective treatment but for which observations suggest that patients suffer no such reduction of healthspan 59 or lifespan. We might then ask what counterbalancing effect is negating the expected effect of the pathology, and test whether this is beneficial in animal models, as was done with PF4 in mice. A search would be crossdisciplinary, requiring a combination of pathology to predict what the outcome of a known pathological process is expected to be, epidemiology to establish that morbidity or mortality from that process is substantially less than expected, and then basic science to explore how a protective effect may be exerted, and whether that can be converted to a therapeutic strategy. In the case of ET, the known effect of disorder of the clotting system in causing thrombotic events would predict that people with ET would have a reduced life expectancy; however, this expectation of not borne out. It was this serendipitous observation that led this author to explore aspects of platelet biology that may be life-preserving. Another example may be the apparent protective effect of ascending aortic aneurysms for atherosclerotic disease. 60 Aortic aneurysms result in significantly reduced life expectancy 61 but ascending aortic aneurism may not. The mechanism for this has not been identified but could be a productive area of research into the prevention or treatment of atherosclerosis. There may be other examples awaiting serendipitous discovery.
Conclusion
This article presents the concept of APaP, the observation that a pathogenic process can have compensating beneficial effects on unrelated systems, and as a result cause less morbidity and mortality than would otherwise be expected. Looking for examples of APaP could lead to the discovery of novel therapeutic approaches. Essential thrombocythemia may be an example of APaP, which has testable consequences for the management of the condition, and for the potential beneficial role of PF4 as a treatment for some age-related pathologies.
Footnotes
Acknowledgments
The author thank Dr. Janette Thomas (Five Alarm Bio Ltd) for encouragement to write up this hypothesis and an anonymous reviewer for help with the structure of this article.
Author’s Contribution
The sole author of this article was responsible for Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, and Writing—Original Draft and Review & Editing.
Author Disclosure Statement
The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the article; or in the decision to publish the results.
Funding Information
This work was supported by Five Alarm Bio Ltd. (Cambridge, UK).