The Impact of Hormesis upon Clinical Aging: History
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Contributor:
Marios Kyriazis
,
Lama Swas
,
Tetiana Orlova

Digital information technology is placing an increased cognitive load on our neurons. This enriched environment, provides ‘information-that-requires-action’, which acts through hormesis and activates the neuronal stress response. As a result, human neurons are under continual pressure to maintain themselves. Thus, repair resources must be allocated preferentially to the neuron, at the expense of the germline, through the bidirectional cross-talk between neuron vs germline. The result of this hormetic cognitive stress may be a reduction of age-related degeneration, which lasts indefinitely, with a corresponding reduction in reproduction.

  • hormesis
  • neuronal stress response
  • neuron-germline communication
  • neuron-germline conflict

1. Introduction

From a clinical viewpoint, aging is a process which progressively diminishes the function of the person, resulting in chronic degenerative conditions, until this burden becomes incompatible with life. In this respect, one of the researchers (Kyriazis, 2020) has defined aging as: ‘Time-Related Dysfunction’ [1], with the explanation that:
“This definition implies that, with the passage of time and for a variety of causative factors, humans are subjected to damage which is not properly repaired. As a consequence, there is degeneration and loss of utility at all levels (molecular, cellular, tissue, organismic, and societal) with a resulting failure of the normal function of a human. In other words, it is a chronologically-dependent erosion of our functions, which makes it increasingly difficult for us to manage and operate within a given, always-changing environment”.
Therefore, encouraging specific clinical interventions may positively influence time-related dysfunction and diminish the rate of decline. One such intervention is the use of digital technology which, through the neuronal processing of meaningful information, up-regulates the function of our brain, and may prevent age-related degeneration.

2. Hormesis

During the past several years, there have been many attempts to understand the process of hormesis [2]. Hormesis is a phenomenon in which a low dose of a stressor, such as a chemical or radiation, can stimulate a beneficial response in an organism. Several researchers have proposed that hormesis plays a role in the process of aging [3][4][5]. Hormesis is present in many aspects of the biological world where there is ‘activation’ of a function during application of a low-dose stimulus, and ‘inhibition’ if the dose is increased beyond a certain threshold. It is a non-linear, ‘inverted U’-shaped relationship between dose–effect (Figure 1). Therefore, the principle underlying hormesis is relatively simple: Low dose of a stimulus can positively challenge the organism eliciting a controlled stress response, and result in health benefits, whereas an excessive, suboptimal, or prolonged exposure to the same stimulus can result in damage and disease [6][7]. It should be emphasized that several researchers consider hormesis as a controversial subject, because the original research on hormesis and radiation has not been proven. Nevertheless, an increasing number of other experts, study hormesis as a relevant and valuable subject in health and, particularly, in aging.
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Figure 1. Hormesis: After an initial inhibition at a very low dose, as the dose increases there is a ‘window’ of stimulation, followed again by inhibition at higher doses.
Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food restriction, heat stress, hypergravity, reactive oxygen species, and other challenges, has a variety of anti-aging and longevity-extending effects [8]. Detailed molecular mechanisms that bring about the hormetic effects are still not very clear but are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair [9].
Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in the homeodynamic space (Box 1) of a living system in terms of increased defense capacity and reduced load of damaged macromolecules [10]. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic (but not severe or chronic) physical and mental challenges [7], and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The increasingly established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.
Thus, hormetic stimuli can be nutritional (dietary restriction, intermittent fasting), physical (exercise, heat, cold), chemical (nutritional or pharmaceutical compounds, hormetins), and mental (brain exercises, meditation, cognitive ‘positive-stress’). These may cause a slight injury to the organism, i.e., they disturb homeostasis, thus activating stress response pathways which aim to restore homeostasis, and up-regulate repair mechanisms. During the process of repairing this hormetically-induced damage, any coincidental age-related damage may also be repaired [11].

3. Autophagy and Hormesis

Autophagy is one of the markers of hormesis, i.e., the presence of efficient autophagy indicates that hormesis is occurring, and enhancing the processes of biological repair. Autophagy is a protein turnover pathway, a catalytic process, which aims to degrade and recycle cellular components. This process maintains cellular function during (or after) stress, when damaged material accumulates and it has to be eliminated [12].
The process of autophagy can be enhanced via hormetic stress, such as:
  • Exercise. This can enhance autophagy in liver, muscles, pancreas and adipose tissue, as well as in the brain [13].
  • Moderate hot/cold exposure [14] via activation of Heat Shock Proteins (HSP) [15]. Hormetic stress in addition to HSP involvement, also reduces the progressive accumulation of PolyQ aggregates [16].
  • Intermittent fasting (IF) is a nutritional hormetic stress. Alirezaei et al. [17] conducted a study to investigate the effects of food restriction and short-term fasting on autophagy. Their findings revealed that food restriction induces autophagy in mouse livers, challenging the conventional belief of the brain’s metabolic privilege. Moreover, their research suggests that sporadic fasting could be a cost-effective approach to promote a therapeutic neuronal response. In a separate study, Pietrocola et al. [18] emphasized the significance of autophagy in cancer treatment. They highlighted that impairment of autophagy reduces the effectiveness of chemotherapy and radiotherapy. These findings underscore the importance of understanding autophagic mechanisms to enhance cancer treatment strategies. Additionally, Kim and Lemasters [19] observed the occurrence of autophagy in liver cells during fasting, providing further insights into its role in cellular recycling. Their study demonstrated that liver cells form phagophores and autophagosomes, which encapsulate and capture mitochondria for recycling. This process leads to the breakdown of mitochondria and their contents, including DNA. In addition to physical stimuli, autophagy can be modulated by hormetins, i.e., substances that can induce health-beneficial physiological hormesis [20] and this is an appropriate opportunity to discuss some more details of hormetins.
There are specific stress-induced pathways for enhancing autophagy in neurons [21][22], and it is known that the stress response activates autophagy [23][24][25]. This shows the direct relationship that exists between autophagy and stress. It is therefore reasonable to infer that, if this wide range of hormetic stresses improves autophagy, it could well be that other hormetic stresses, such as a cognitive stress may also have similar effects.

4. Environmental Enrichment

A concept relevant to hormesis is environmental enrichment (EE). This refers to a varied and stimulating environment that promotes physical and psychological well-being. It involves creating an environment that is stimulating and challenging, both physically and mentally. This can include activities such as exercise, social interaction, and learning new skills, as well as exposure to novel and varied stimuli, such as music, art, and digital information that requires a response [26]. The concept of EE has gained prominence in recent years as increasingly more research has demonstrated its benefits for both animals and humans. It can improve cognitive function, reduce stress, and promote natural behaviors. It also improves mood, reduces stress and anxiety, and increases overall quality of life [27].
Studies have shown that animals raised in enriched environments demonstrate better learning and memory, as well as improved problem-solving abilities [28][29]. This is likely because the complexity of an enriched environment provides greater opportunities for cognitive stimulation and growth. In the case of aging, environmental enrichment is becoming increasingly recognized as an effective tool for promoting healthy aging and, specifically, improving cognition [30].
Cognitive stimulation is another key component of environmental enrichment for older adults. This can include activities such as learning a new language, playing a musical instrument, engaging in brain-training exercises, or other virtual or digitally-derived cognitive activities. These activities can help keep the brain active and engaged, promoting cognitive function and reducing the risk of cognitive decline [31]. The new information reaching the brain acts as a hormetic stimulus or a challenge, that activates the neuronal stress response and requires the brain to act in order to deal with this new challenge, through remodeling and increase robustness [26].
It was shown that an environment which is rich in cognitive stimuli, has indirect effects on tissues and organs other than the brain. For instance, some authors have argued that an enriched environment improves vision [32][33], while others reported the benefits of a cognitively enriched environment on:
  • Immunity [34];
  • Wound healing [35][36];
  • The retina [37];
  • Muscle strength, without the need to physically exercise (!) [38];
  • Inflammatory response [39][40] and other physical parameters [41], such as vitality, physical functioning and bodily pain, as well as social and emotional functioning [42]. Many of these effects may persist for several years, in some cases even after a 10 year period [43].

5. Neuronal Stress Response

The neuronal stress response is the set of molecular and cellular changes that occur in neurons in response to stress or injury [44]. These changes help neurons adapt to, and survive, stress, and they can also have important consequences for the function and health of the nervous system [45]. One of the key factors in the neuronal stress response are the stress-response proteins. These proteins are activated in response to various stressors, including heat, cold, radiation, and certain chemicals, as mentioned above. Once activated, stress-response proteins support neurons overcome stress by modifying their gene expression, protein synthesis, and other cellular processes [46][47], such as ATP generation in times of stress [48] and the modulation of the signaling molecule cyclic AMP [49]. It is important to note that the neuronal stress response is not a uniform process, and different neurons may respond to stress in different ways depending on their specific function and location in the nervous system. Additionally, the response to stress can vary depending on the severity and duration of the stressor, as well as the genetic and environmental background of the organism.

6. Digital Information, Cognition, and Neuronal Stress Response

The advent of information technology has brought about a significant rise in the cognitive load imposed on our brains, primarily due to the sheer volume of information we now encounter [50]. The internet and social media platforms offer us access to an overwhelming abundance of information, making it increasingly difficult to sift through and identify what is truly important and relevant. As a result, individuals often struggle to concentrate on productive and meaningful tasks as they grapple with the challenge of filtering out the noise and distractions surrounding them [51].
This can lead to cognitive overload, which can impair cognitive function and lead to feelings of stress and fatigue. Our neurons are subjected to the phenomenon of ‘neuronal fatigue’ and they stop responding to an unchanged, continual monotonic stimulation. Such a stimulation causes the neuron to lose its ability to transmit activation to other neurons [52]. On the other hand, a moderate (in other words, hormetic) amount of information that requires us to act, may impact positively on the brain, up-regulating the neuronal stress response and thus enhancing the robustness of neuronal function [53]. In essence, we are living in an enriched environment, as described above.
We know that digital cognitive training improves cognition and may reduce the risk of dementia [54]. Studies have repeatedly shown that ‘serious games’ have a positive impact on dementia patients [55][56]. ‘Serious games’ are participative digital/electronic games designed for purposes other than entertainment. Specifically, Yang et al. [57] state that there is:
“…evidence that video game interventions could be considered for the elderly for improving performance and cognitive function, especially general cognitive scores and processing speed. Games with better interactivity and visual stimulation have better curative effects…”.
In addition, electronic games used generally for entertainment also have positive effects on the memory of older people [58][59].
By being exposed to a judicious, ever-changing, novel and positive amount of information, it becomes necessary for our neurons to acquire additional repair resources and thus function for longer, with a consequent overall improvement in healthy lifespan. These additional energetic resources are subjected to a trade-off: as a balancing (trade-off) measure, germline repair mechanisms need to be down-regulated to accommodate a corresponding escalation of repairs in neurons [60]. This is because there is a close relationship between neurons and germline cells.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12165433

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