Lifestyle Changes in Aging and their Potential Impact on POAG

Abstract

Primary open angle glaucoma is a primary mitochondrial disease with oxidative stress triggering neuroinflammation, eventually resulting in neurodegeneration. This affects many other areas of the brain in addition to the visual system. Aging also leads to inflammaging – a low-grade chronic inflammatory reaction in mitochondrial dysfunction, so these inflammatory processes overlap in the aging process and intensify pathophysiological processes associated with glaucoma. Actively counteracting these inflammatory events involves optimising treatment for any manifest systemic diseases while maintaining chronobiology and improving the microbiome. Physical and mental activity also provides support. This requires a holistic approach towards optimising neurodegeneration treatment in primary open angle glaucoma in addition to reducing intraocular pressure according personalised patient targets.

Keywords

Glaucoma - aging - neurodegeneration - chronobiology - microbiome - physical activity

Introduction

Primary open-angle glaucoma (POAG) is the most common form of glaucoma in Europe at 74% [1] and is associated with increased intraocular pressure (IOP) at approximately 70%. Patients with normal-tension glaucoma (NTG) without statistically increased IOP make up the remaining 30% [2]. NDG is considered more of a “small-vessel” disease [3] that is pathophysiologically distinct from POAG; we will not be covering it any further in this overview.

According to current knowledge, POAG is classified as a primary mitochondrial disease [4], [5] with genetic mutations in mitochondrial DNA leading to a 21% reduction in mean mitochondrial respiratory activity [6]. Changes in OPA-1 gene [7] activity and/or cholesterol 24S-hydroxylase gene polymorphism [8] cause further mitochondrial respiratory impairment. Manifestations of the associated mitochondrial dysfunction include reduced free-radical metabolism leading to increased oxidative stress, reduced ATP production, cellular plasma membrane instability with uncontrolled influx of messenger substances and calcium into the cells, and development of metabolic dysfunction [9]. This results in excessive cellular immune response and inflammatory reaction, which precipitates cellular aging and apoptosis. These inflammatory processes have been demonstrated in POAG [10] causing neuroinflammation [11], which leads to neurodegeneration [12]. POAG is also associated with many systemic diseases including arterial hypertension, diabetes mellitus, and dyslipidaemia [13], [14]; these conditions lead to secondary mitochondrial disease [15], [16], [17], thus exacerbating the primary mitochondrial disease in POAG.

POAG involves generalised neurodegeneration leading to a reduction in the lateral geniculate body, optic nerve, visual cortex, and involvement of the entire brain [18], [19]. More than ten different brain areas outside the visual cortex have so far been associated with significant changes such as altered spontaneous brain activity, altered functional connectivity, and decreased grey matter volume [19]. Visual perception involves around 60% of the entire brain [20], giving rise to additional clinical manifestations that are often challenging to classify alongside classic visual field defects; these manifestations include reduced reading speed, disturbance in stereo vision, and early contrast and colour vision disturbances [21].

Apart from that, intracranial pressure is reduced in POAG [22], leading to increased translaminar pressure difference (ocular pressure minus intracranial pressure). This in turn causes greater transverse load on the lamina cribrosa with an adverse effect on glaucomatous optic neuropathy [23]. However, the mechanism behind the reduction in CSF pressure is still unclear. Reduced CSF production due to neurodegenerative changes in the choroid plexus, the site of formation of the CSF, has been proposed as a possible cause; on the other hand, compartment syndrome in the subarachnoid system within the optic canal has already been demonstrated [24]. Either way, glymphatic system impairment in POAG has also been discussed [25]; the section on maintaining chronobiology covers this in more detail. Synaptic dysfunction has also been identified [26] with β-amyloid and hyperphosphorylated tau deposits detected in the retina; these lead to manifestations such as substantial microglial activation [27]. Apart from neurodegeneration, generalised endothelial dysfunction, blood-brain barrier dysfunction, and enteric microbiome disruption have also been identified [28]. Finally, a recently published study has found glaucoma patients to be at increased risk of Alzheimerʼs disease and vascular dementia [29].

Aging is also associated with increased POAG prevalence [30], [31]. Aging is more of a risk factor for this form of neurodegeneration, as is the case with many other neurodegenerative diseases such as Alzheimerʼs and Parkinsonʼs disease [32].

Aging is now understood to be a highly complex process consisting of the following individual processes according to current knowledge [33]:

• Genomic instability

• Telomere attrition

• Epigenetic changes

• Mitochondrial dysfunction

• Impaired autophagy

• Proteostasis loss

• RNA processing dysregulation

• Impaired nutrient sensitivity

• Cellular senescence

• Stem cell exhaustion

• Altered intercellular communication

• Microbiome disruption

• Alterations in biomechanical properties

• Vascular endothelial dysfunction

All these processes occur at varying levels of intensity but interact with one another, leading to chronic, sometimes subclinical signs of inflammation collectively known as inflammaging [34]. The result is a substantial increase in chronic diseases such as diabetes mellitus type II, dyslipidaemia, arterial hypertension, and chronic kidney disease [35], [36].

Even so, senescence is still largely unexplained as a biological process that is considered to be highly heterogeneous and multifactorial, raising many questions that have so far remained unanswered [37]. There is even controversy as to the point at which aging begins [37]. Aging processes can already be biochemically and structurally detected from the age of twenty-four [38].

POAG is mainly a mitochondrial disease, so the total numbers of mitochondria are also subject to these age-related changes. A mitochondrion is a cell organelle enclosed by a double membrane, and it contains its own genetic material as mitochondrial DNA. This organelle is involved in a host of essential metabolic processes such as the citric acid cycle, phospholipid synthesis, apoptosis signalling pathway, and above all, the mitochondrial respiratory chain [39]. Free radical metabolism takes place in the mitochondrial respiratory chain, releasing energy directly and indirectly in a biochemically available form as adenosine triphosphate (ATP), which is the cellʼs universal energy carrier. The total mitochondrial surface area in an adult amounts to around four football fields, reflecting the vital role that mitochondria play in cellular metabolism [40].

The mitochondria need coenzyme Q10 (CoQ10), which plays an essential part in the mitochondrial respiratory chain. This coenzyme is an essential component in mitochondrial enzyme complexes and is indispensable in ATP production. As such, CoQ10 plays a major role in cell vitality. CoQ10 is an endogenous molecule that is synthesized in the liver [41]. However, the liver produces less with age; CoQ10 concentrations in the heart of a healthy 40-year-old are only 68% of those in a healthy 20-year-old [42]. This aging process has also been demonstrated in the choroid and the retina, as an 80-year-old has only 60% of the CoQ10 concentration in either tissue compared to a 30-year-old [43]. CoQ10 is available as a dietary supplement; the tablet dosage should be 50 – 100 mg/day as the enteral absorption rate is only around 30% [41].

But what influences do positive lifestyle changes have on aging and POAG?

Optimising Management of Existing Systemic Diseases

Aging comes with a substantial increase in chronic systemic diseases [36] that greatly promote the aging process through inflammaging [44].

Arterial hypertension occurs in around 50%, diabetes mellitus in 22 – 30%, and dyslipidaemia in 20 – 30% of POAG patients [45], [46]. Optimising systemic disease treatment greatly contributes to a general improvement in neurodegenerative processes. Average values should not exceed 120/80 mmHg in treating arterial hypertension, blood pressure fluctuation should not exceed 30%, and day-night fluctuations should not be less than 10% (non-dippers) and not more than 20% (extreme dippers) [47]. In particular, low diastolic blood pressure values below 60 mmHg are unfavourable and may negatively affect glaucoma progression [48], but also promote dementia development [49]. Orthostatic hypotension plays an especially important role in this [50].

HbA_1c values should not be below 6% to avoid hypoglycaemia in elderly patients with diabetes mellitus. The optimal range lies between 7% and 8% [51], [52].

LDL cholesterol levels less than 100 mg/dl are recommended in patients with POAG and dyslipidaemia, and levels less than 55 mg/dl in patients with manifest vascular diseases [53].

Maintaining Chronobiology

Chronobiology refers to how biological systems are organised over time and covers regular biological processes and rhythmically recurring factors in the way individuals live. Part of the hypothalamus, the suprachiasmatic nucleus plays a major role as a biological clock in humans. All organ systems also have their own clocks in the form of aptly named CLOCK genes, which work independently of one another [54]. Typical chronobiologically controlled processes include intraocular pressure, heartbeat, breathing, sleeping, and hormonal processes such as the menstrual cycle. Aging disrupts chronobiological processes partly due to a lack of melatonin [55]; this can lead to changes in neuroimmunological homeostasis [56], thus promoting neurodegenerative processes [57]. Melatonin is also involved in brain detoxification from metabolic end products through the glymphatic system [58]. The glymphatic system is a perivascular space filled with cerebrospinal fluid around the cerebral arteries and veins connected to the subarachnoid space and is directly connected to the optic nerves. This system is responsible for disposing of cellular waste products in the central nervous system (CNS). This process almost only occurs during sleep [59]. Age-related melatonin deficiency disrupts this cleansing process, thus promoting neurodegenerative disease development [58], [60]. Melatonin exhibits antioxidant properties and contributes to mitochondrial function stabilisation [61], so melatonin deficiency is considered to be one of the factors involved in the connection between the glymphatic system and mitochondrial dysfunction [61], [62].

Sleep quality also changes with increasing age; this includes sleep efficiency and duration [63]. A normal healthy adult will sleep between seven and nine hours [64]. Reduced sleep duration increases cardiovascular risk [65]. Sleep disorders are also associated with an increase in neurodegenerative diseases [66], as shorter sleep duration also disrupts cerebral cleansing by the glymphatic system. Apart from that, sleep disorders are associated with reduced neuronal growth factor BDNF (brain-derived neurotrophic factor) levels in serum [67]; BDNF plays a role in synaptic activity as well as functional and structural plasticity in the CNS [68]. Reduced BDNF serum levels are considered to be a biomarker in cognitive and sensory neurodegeneration [69].

Chronobiology is also disrupted in POAG [70], which is partly due to impairment in the intrinsic photosensitive retinal ganglion cells [71], and also partly due to cerebral and visual impairment. Both melatonin [72] and BDNF [73] play an important role in the POAG chronobiology.

This has important ramifications in POAG:

• Familiar diurnal intraocular pressure patterns can change with age; effects might include IOP in a patient peaking at 10 PM when it used to peak at 4 AM. This could lead to an incorrect assessment for effective treatment, as these pressure peaks at evening or during the night cannot be recorded outside normal practice hours.

• Sufficient and regular sleep is important in a disrupted glymphatic system. Melatonin is considered to play a great role in this, so it could be used as a supplement in treating glaucoma [72]; as such, this supplement promises to be an effective adjuvant treatment option, especially in patients with major sleep disorders. In Germany, melatonin is available as a dietary supplement and as a prescription drug in sustained-release form.

• A balanced diet is of great importance in nutrition. Chrononutrition, a relatively new branch of research, has shown different eating habits at different times to lead to different gene activations [74], [75]. It would therefore be advisable to eat at regular intervals and avoid numerous snacks.

Maintaining a Healthy Enteral Microbiome

The human enteral microbiome covers the totality of all microorganisms in the human intestine, especially the large intestine. More than a hundred million individual bacteria from more than a thousand different species live in the intestine. The responsibilities of the microbiome include controlling digestion, regulating the intestinal wall barrier, inhibiting and activating various metabolic pathways, stimulating intestinal motility, and absorbing nutrients and energy. The enteral microbiome is also immunologically active as it prevents harmful organisms from penetration, activity and growth, promotes protective factor formation in the intestinal mucosa, exhibits its own antimicrobial effects, and limits inflammatory mediator formation [76]. Various microbiome axes have been found in the human body, such as the microbiome-brain and microbiome-eye axis [77], [78].

Many factors can have an adverse effect on the microbiome. Apart from the classical harmful influences such as smoking and alcohol, which both adversely affect microbiome composition [79], [80], [81], eating habits such as fast food are also harmful to the microbiome [82]. The resulting change in enteral microbial composition leads to chronic intestinal wall permeability disorder, which also leads to reduced short-chain fatty acid production while also activating inflammatory processes. Short-chain fatty acids are unbranched saturated fatty acids with a short chain length of 2 – 6 carbon atoms [83]. These fatty acids are formed in the intestine from indigestible carbohydrates (fibre and digestion-resistant starches) by the intestinal flora and absorbed via monocarboxylate transport proteins in almost all tissues, including the brain [84]. The fatty acids are also involved in regulating appetite and energy metabolism in the brain [85], [86] and may also help prevent and improve metabolic diseases such as diabetes mellitus type II and obesity [87]. Reduced short-chain fatty acid production due to a microbiome disorder may lead to cerebral energy supply issues alongside autoimmune diseases [88]. There are also connections between the microbiome and a variety of systemic diseases such as diabetes mellitus [89], arterial hypertension [90], and dyslipidaemia [91].

The human enteral microbiome undergoes a shift in microbial biodiversity with age; this leads to overexpression of pathogenic bacteria, reduced short-chain fatty acid production, altered intestinal mucosa, and increased permeability in the intestinal wall [92], [93], [94]. The causes are partly due to changes in eating habits and chronobiology as well as restricted physical mobility, along with increased systemic diseases and the associated variety of medications they require. These changes lead to immune system dysregulation with low-grade chronic inflammation [95], [96]. The immunological changes involved lead to neuroinflammation with subsequent cerebral neurodegeneration [97]. In this context, the bacterial and cellular remodelling processes in the intestine are closely linked to classical neurodegenerative diseases such as Alzheimerʼs and Parkinsonʼs disease [98], [99].

A meta-analysis has also shown a statistically significant association between POAG and bacterial infection with gram-negative Helicobacter pylori [100]. Lipopolysaccharide (LPS), a major outer cell wall component in Gram-negative bacteria, has an adverse effect on the intestine [101] by increasing enteral permeability, thus activating the immune system [102]. Helicobacter pylori also causes atrophic gastritis, which leads to a deficiency in folic acid and vitamin B₁₂. This pathway may trigger hyperhomocysteinaemia [103], which is associated with both neurodegeneration [104], [105] and POAG [106]. In any case, Helicobacter pylori should be investigated as a possible cause for neuroinflammation in progressive glaucoma towards initiating treatment as appropriate.

Improving the enteral microbiome is considered a positive lifestyle change for both aging and POAG. This includes measures such as regular food intake at set times (see above), preferably with a Mediterranean diet [107], especially as it may improve mitochondrial dysfunction [108]. Eating plenty of vegetables and fruit is also recommended. The German Nutrition Society recommends a “five a day” regime with three portions of vegetables (approx. 400 g) and two portions of fruit (approx. 250 g) as far as possible [109]. Seasonal products have short transport routes and preserve as many of the vitamins as possible, so these should be the first choice. High-quality oils may also be beneficial, such as olive oil with its anti-inflammatory properties [110] as well as probiotics – live microorganisms that may provide health benefits by promoting a favourable balance in the enteral microbiome. One such probiotic source worth mentioning is kefir, a well-defined composition of certain bacterial strains [111] with antioxidant, anti-inflammatory, and antimicrobial properties [112]. There is also discussion on the possibility of achieving the effective levels of vitamins and other active ingredients as required using dietary supplements. The recommended daily dose of Vitamin C from the age of eighteen is 110 mg/day for men and 95 mg/day for women [113]. Vitamin C concentrations in apples vary between 0.05 mg/100 g and 0.96 mg/100 g by weight depending on apple variety [114]. At an average weight of 200 g for a medium-sized apple, 100 apples a day should suffice under optimal conditions (fresh, short transport route, good storage conditions). However, natural and synthetic vitamin C show no difference in bioavailability in humans, so taking vitamin C as a dietary supplement is an acceptable alternative source [115]. Physical activity also has a positive effect on the enteral microbiome [116]. Integrating all this knowledge into a viable concept acceptable to a patient requires the assistance of an experienced nutritionist with an overall target in mind and a step-by-step therapy plan so as not to overwhelm the patient.

Physical Activity

Many remodelling processes develop in the musculoskeletal system during aging, some of which are caused by loss of muscle mass and osteoporosis. Together with coordination and balance disorders, this remodelling process increasingly places limits on mobility in old age; this is associated with increased risk of developing coronary heart disease, type II diabetes mellitus, cancer, and shortened life expectancy [117], [118]. In addition, reduced physical activity causes social isolation, which further affects hormonal, immunological, and neuronal balance [119], [120].

Optic neuropathy and involvement of the visual cerebral system in POAG lead to many visual impairments such as visual field restrictions, disturbances in stereo vision, disorders in the perception of colour and contrast, and increased sensitivity to glare [21]. This results in reduced physical activity [121] and gait issues [122].

Promoting physical activity specifically tailored to the personal situation of the POAG patient is therefore advisable, regardless of age. Physical therapists are usually in a good position to provide a physical therapy plan.

The positive effects of physical activity are obvious and include favourable effect on motor performance [123], improvement in the microbiome [124], increased BDNF release [125], less pronounced cardiovascular disease [126], and above all, improvement in neurodegenerative diseases [127]. The WHO published guidelines on physical activity and sedentary behaviour in 2020 [128] recommending at least 150 – 300 minutes of moderate endurance exercise for older adults (> 65 years), or at least 75 – 150 minutes of intense physical exercise per week. According to recommendations, weight training should include exercises for all major muscle groups at least twice a week; sedentary periods should be reduced and replaced by physical activity of any kind; and balance exercises and strength training towards avoiding falls should be carried out at least three days a week.

A reduction in intraocular pressure has ben observed in POAG, especially in endurance sports [129]. Even so, a blanket recommendation for more physical activity is inadvisable; the exercise selected needs to take the patientʼs current overall oxygenation situation into account. As an example, endurance training is beneficial in high blood pressure whereas patients with low diastolic blood pressure below 60 mmHg should engage in light strength training to keep blood pressure from lowering even further. Not overdoing it is also important; exercise to the performance limits and exhaustion may trigger a massive increase in systemic oxidative stress [130]. On the other hand, fat oxidation is more effective at 10,000 steps per day compared to 2,000 steps per day [131].

Mental Activity

Aging is often associated with a decrease in mental activity [132]. The glymphatic system appears to play an important pathophysiological role in this. Sleep changes, inflammaging, and their comorbidities lead to glymphatic system impairment, which in turn increases the occurrence of mental disorders [133]. Increasing inflammation leads to microglial activation and changes in synaptic plasticity, which is associated with accelerated mental aging [134] and further exacerbated by vascular impairment [135].

Cognitive dysfunction has also been demonstrated in POAG [136]; this is associated with reduced stress coping strategies [137] leading to personality disorders [138] and an increased tendency towards depression [139]; mental aging also plays a major role in POAG.

Recent work has shown it to be possible to counteract this process with a favourable outcome. A sense of discovery promotes mental processes [140] as does learning new skills such as language, musical instruments, and painting [141], [142]. Social integration plays an especially important role in mental well-being [143]. Cognitive training provides more effective support for mental rather than physical activity [144].

Outlook

POAG has undergone a profound change in the way we view the disease over the last twenty years. The classical concept of localised optic neuropathy has been abandoned in favour of systemic neurodegeneration originating in a primary mitochondrial disease with subsequent neuroinflammation. Therapeutic treatment concepts in the future will need to be implemented on a far broader footing in addition to the established treatment of reducing intraocular pressure to the patientʼs target pressure range. The European Glaucoma Societyʼs lack of recommendation to reduce intensive intraocular pressure reduction in older POAG patients is difficult to understand, especially in view of inflammaging and the resulting increased sensitivity of tissue to intraocular pressure [145] – these particular patients suffer the most damage from increased intraocular pressure. Advanced age in the elderly is no reason to limit treatment intensity considering the implausibility of predicting life expectancy in individual cases.

Developing a personalised holistic treatment and therapy concept for each individual POAG patient will play a major role in addressing the complex pathogenesis of generalised neurodegeneration. Any such concept must include social environment by involving the patientʼs life partners, family members, and friends.

Conclusion

Already known:

• Increased age is a risk factor for POAG.

• Aging is a highly complex process.

• Familiar measures towards slowing down aging include optimised therapy for manifest systemic diseases as well as physical and mental activity.

New:

• POAG is a neurodegenerative disease.

• Aging leads to chronic subclinical inflammation, known as inflammaging.

• New areas of focus for slowing down aging include maintaining chronobiological processes and maintaining a healthy enteral microbiome.

Conflict of Interest

Erb: Consulting for AbbVie, Santen and OmniVision. Lectures at AbbVie, Thea, Santen, Ursapharm.
The other authors declare that there is no conflict of interest.

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Publication History

Received: 17 December 2023

Accepted: 19 July 2024

Article published online:
27 August 2024