It is generally considered that ageing is a multifactorial process1,2. However, nearly all existing theories ultimately require molecular damage to be the initial cause1. In DST for example, Kirkwood3 posited that investing in maintenance is energetically costly, and therefore molecular damage could be allowed to accumulate if that energy could be better utilised in other processes with greater impact on fitness (e.g. growth and reproduction). While Kirkwood1 suggested multiple molecular mechanisms were likely to be involved in ageing, including telomere attrition, protein aggregation, and mitochondrial dysfunction, all the suggested mechanisms were based on molecular damage, and ageing would thus reflect “multiple kinds of damage”. However, if that is true then at its core, ageing reflects only one single cause: that organisms do not invest sufficiently in maintenance to prevent damage accumulation. Indeed, few hypotheses suggest how ageing could result without damage accumulation.
The main exceptions are mutation accumulation theory (MAT) and antagonistic pleiotropy (AP). The former suggests that high extrinsic mortality in the wild would allow for ageing-inducing mutations as the forces of selection would decline over an organism’s lifespan4. Initially, the idea was attractive because ageing was not believed to occur in the wild4. However, it is now accepted that ageing does occur in the wild in multiple species5. In contrast to MAT, AP suggests that pro-ageing mutations offer a fitness advantage earlier in life when selection is stronger6. As with MAT, there are also multiple SNPs in humans that may contribute to early life fitness at the cost of fitness later in life7, and predictably, these mutations have detrimental effects significantly earlier. However, while such SNPs may explain the onset of some diseases in some individuals, it is more difficult to identify ancient mutations that are now universal, inducing ageing via a consistent mechanism across species and organisms. As such, these theories currently provide a clearer view of the evolutionary framework that may allow ageing to evolve rather than a comprehensive biological mechanism.
Here, we attempt to outline an antagonistically pleiotropic biological process that could induce ageing independently of damage accumulation and the energetic costs of maintenance. As such, we believe selective destruction theory (SDT) to provide the first comprehensive mechanism that would provide ageing organisms with a fitness advantage over similar organisms undergoing negligible senescence (without dependence on damage accumulation). However, it is not mutually exclusive with damage-centric theories.
Over time, cells can undergo permanent or semi-permanent changes that affect their rate of growth and proliferation. These could reflect mutations or epigenetic changes, but the altered cells will henceforth be referred to as mutants for simplicity. Such mutants are either aberrantly sensitive (AS) or aberrantly resistant (AR) to growth signals compared with wildtype cells. While both AR and AS mutants reduce tissue functionality by responding incorrectly to the environmental cues, AR mutants will grow and proliferate slower than wildtype cells (non-mutants), putting them at a selective disadvantage, whereas AS mutants will grow and proliferate faster, giving them a selective advantage over wildtype cells and AR mutants. AS mutants are therefore a threat to tissue homeostasis in a way that AR mutants are not. If they are not controlled or removed, they will outcompete the wildtype cells and may become the dominant cell type (Figure 1A).
The accelerated growth and division of AS cells would be associated with a faster mutation rate, as can be seen under extreme examples such as RAS and RAF mutations which induce a state of hyperproliferation associated with high levels of DNA damage8. While these extreme mutations induce senescence9, for reasons described below, mutations with milder effects on growth cannot autonomously stop their own growth. Therefore, if left uncontrolled such mutants could undergo successive mutation and transformation.
Fibrosis is a highly metabolic process requiring mTORC1 signalling through the inhibition of eIF4E-binding protein 1 (4E-BP1) to produce the large amounts of extra cellular matrix (ECM) proteins10. In some mesenchymal cell types, AS mutants with faster metabolism and more active growth pathways could therefore be expected to increase the risk of fibrosis. For example, insulin-like growth factor-1 (IGF-1) is a key growth factor inducing growth and proliferation, which also stimulates the survival and activation of fibroblasts, causing differentiation to highly fibrotic myofibroblasts11,12. AS mutants in IGF-1 signalling would therefore proliferate and activate in response to weaker signals, making it more likely that they would reach the critical mass required for fibrosis13. Patients with systemic sclerosis and idiopathic pulmonary fibrosis (IPF) both have high levels of serum IGF-114, indicating that these lethal diseases involve increased activation of this pathway which would be associated with AS mutants. Notably, around 45% of all deaths in the developed world are ascribed to chronic fibroproliferative diseases15.
However, while fibrosis is an important metabolic process, and fibroblasts or pro-fibrotic cells are present across multiple tissues and organs, it is not the only example of cell function that might be upregulated in AS mutants. AS mutants of many cell types are likely to increase their specific functional output as growth and proliferation are usually part of the mechanism to increase long-term production/activity, so the pathways which increase one will increase the other16. For example, b cells proliferate and produce insulin when blood glucose is high, and trigger apoptosis and inhibit insulin when glucose is low. The insulin production pathway is therefore intertwined with the growth and proliferation pathways17 so both can be up or downregulated together in response to stimulus. However, as the human body requires blood glucose to remain at around roughly 5 mM, Karin and Alon16 identified that mutants sensing blood glucose at an incorrectly high level would quickly cause death if they were allowed to spread. This would happen for two reasons. Firstly, these mutants hypersecreting insulin can lower blood glucose below the point at which the rest of the body’s tissues can sustain respiration. Secondly, the wildtype cells sensing the correct level of glucose undergo apoptosis to reduce insulin production, hastening the spread of mutants and the lethal drop in blood glucose. Thus, any cell type that utilises cell division as a mechanism to regulate functional output, and whose functional output relies on keeping metabolites, proteins, and even other cell types within a certain range, is threatened by AS mutants. Even if the outcomes are not lethal, as they are for fibrosis, insulin production, and other pathways such as calcium homeostasis, they will not promote good health or bodily function.
AS mutants will therefore promote morbidity and mortality through cancer, fibrosis, and overactivity (CFOA). From this, we conclude that organisms would gain a fitness advantage from controlling AS mutants, and the stricter the control mechanisms, the longer an organism could hope to retain wildtype functionality and avoid CFOA. There are two possible mechanisms of controlling mutants with a selective advantage, but both require a marker of phenotypic change: as here we are concerned with sensitivity to growth, we have termed this a growth marker (GM). Firstly, cells could autonomously recognise that the absolute concentration of the GM they are expressing is too high and induce their own apoptosis. Oncogenic mutations in RAS, AKT, PI3K, and multiple other mitogenic molecules have been shown to induce senescence and apoptosis depending on cell type and severity18. Hypersecreting b cell mutants also undergo apoptosis (termed glucotoxicity)16.
Importantly, autonomous mechanisms allow both AS and AR mutants to be removed with equal efficiency as cells recognise their own absolute value of GM (Figure 1B). However, such mechanisms are intrinsically dangerous: in the case of b cells, glucotoxicity in hunter gatherers would have removed only dangerous mutant cells producing too much insulin, but modern diets rich in calories and refined sugars are inducing glucotoxicity in wildtype cells which are producing high levels of insulin to remove the high levels of glucose in the blood, thus resulting in pancreatic destruction and type II diabetes16. The danger arises because autonomous mechanisms are incapable of distinguishing between aberrant cells and aberrant conditions, so any autonomous mechanism must only activate in conditions that are highly unlikely to occur in nature. Consistently, type II diabetes was likely a rare condition before the introduction of refined sugars19.
Less severe mutants must be controlled by a second non-autonomous method via comparison with the surrounding tissue. For example, tumour cells are distinguished from surrounding tissue by natural killer (NK) cell recognition of MHC class I chain-related protein A (MICA) levels20. In the case of b cells, only the most extreme hypersecreting mutants induce glucotoxicity, so there is still a range of mutants which cannot be removed this way, but still have a selective advantage over wildtype cells. Korem Kohanim, et al. 21 suggested a system of immune control called the autoimmune surveillance of hypersecreting mutants (ASHM) for their control: autoimmune T cells would compare the level of pro-insulin expressed by b cells before killing the cell expressing the highest levels. Thus, if a mutation increasing insulin production has occurred in a cell, then it would likely be killed first.
For AS mutants, when correctly calibrated, an ASHM-like mechanism could return the selective advantage to wildtype cells, as shown in Figure 1C (top). However, as also shown in Figure 1C (bottom), such selective destruction of the fastest growing cells is incapable of removing the slow growing AR mutants, which will slowly replicate over time until they begin to outnumber wildtype cells in certain areas. At this point, the immune cells would then recognise the AR mutants as wildtype and the wildtype as AS mutants, providing a selective advantage to the AR mutants.
Importantly, in the model of hypersecreting b cells described by Korem Kohanim, et al.21, the spread of hypo-secreting mutants was unlikely because such cells preferentially induced apoptosis as part of the mechanism to raise blood glucose22. Severe AR mutants may also undergo apoptosis due to lack of mitogenic signals, but moderate mutants are likely to persist if the soma uses a system of selective destruction for mutant control. Attempting to remove AR mutants by either autonomous or comparative mechanisms could have serious repercussions: ASHM, for example, has been implicated in type I diabetes through the immune destruction of healthy b cells21 because chance events such as infection lead to the identification of healthy β cells as hypersecreting mutants, causing the destruction of the pancreas.
Therefore, we hypothesised that no changes to the process of selective destruction could result in a more favourable outcome for the organism. The options would be threefold:
Spread of AS mutants resulting from their selective advantage. The result is death from CFOA at an early age.
Autonomous control of AR and AS mutants even for low level changes. The result is death from en masse apoptosis and senescence when changes in environmental conditions cause wildtype cells to be mistaken for mutants.
The selective destruction (SD) of AS cells which allows AR mutants to spread. The result is slow functional decline (ageing).
From the three possible outcomes, ageing would provide the greatest fitness advantage, while the rate of ageing would depend on the severity of the SD control mechanism. To address whether this was true in practise we constructed a series of models to address if:
SD would prove better at mutant control than unselective destruction (UD) i.e. equal attempt to remove both AS and AR mutants.
If implementing SD would induce ageing as predicted via the spread of AR mutants.
If SD involved an immune surveillance mechanism similar to that described by Korem Kohanim, et al.21 for the comparative control of hypersecreting mutants, it would likely work mainly via inducing apoptosis. However, we considered that while such a process might work well for the regulation of the small populations of cells in pancreatic islets, it was unlikely to be the central mechanism across multiple organs and tissues maintained by selective destruction, particularly among simpler creatures with more primitive immune systems that nonetheless still age.
Instead, we hypothesised that selective destruction could be implemented by juxtacrine and paracrine signals from cells within the same tissue. Speculatively, neighbouring cells could communicate their relative level of metabolism by the levels of GM, and influence each other’s fate accordingly, with slower cells suppressing the growth potential of faster cells through epigenetic modification, senescence, or apoptosis.
Notch signalling controls juxtacrine communication, and consistently, Notch mutations are associated with the clonal expansion of leukaemia cells23 as well as skin and lung squamous cell carcinomas24, which may implicate that these cells are escaping attempts of their neighbours to suppress their clonal advantage, highly consistent with SDT. Indeed, evidence suggests that Notch mutations aid tumour formation via non-autonomous signals from the tumour microenvironment25, while Notch signalling plays a key role in senescence by mediating juxtacrine signalling26.