EDITORIAL |
https://doi.org/10.5005/jp-journals-10078-1451 |
Reversing Aging and Improving Health Span in Glaucoma Patients: The Next Frontier?
1Department of Ophthalmology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
2Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3Department of Ophthalmology and Community Outreach, Marengo Asia Hospitals, Gurugram and Faridabad, Haryana, India; Mayo Clinic, Jacksonville, Florida, United States
Corresponding Author: Tanuj Dada, Department of Ophthalmology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India, Phone: +91 9873336315, e-mail: tanujdada@gmail.com
How to cite this article: Dada T, Mahalingam K, Bhartiya S. Reversing Aging and Improving Health Span in Glaucoma Patients: The Next Frontier? J Curr Glaucoma Pract 2024;18(3):87–93.
Source of support: Nil
Conflict of interest: None
INTRODUCTION
Glaucoma is a chronic progressive optic neuropathy characterized by degeneration of retinal ganglion cells (RGC) and its axon causing optic nerve cupping and associated visual field defects.1-9 In glaucoma, initially, there is the death of RGC associated with damage to the retinal nerve fiber layer (RNFL) and optic nerve head (structural changes), leading to visual field defects (functional changes). Many studies also suggest that the structural changes precede the visual field changes in glaucoma. Although intraocular pressure (IOP) control is the mainstay of treatment, glaucoma progression can occur even after adequate IOP control.2-9
Glaucoma is an age-related noncommunicable disease—part of the bouquet of diseases that affect some, but not all, elderly. While aging is an immutable, and irreversible deterioration in physiological homeostasis and function due to changes at the cellular level, it is exaggerated in the case of disease. The factors that may be responsible for the development of glaucoma at the cellular level include oxidative stress and mitochondrial dysfunction as well as protein misfolding. Possible alterations in cellular milieu that could contribute to glaucoma include excitotoxicity, altered neurotrophin signals, and hypoxic and ischemic injuries.8
Various neuroprotective strategies have been proposed to prevent RGC apoptosis, but IOP lowering is the only practical therapy.10-16 As apart from glaucoma, the aging process can also contribute to the RNFL loss/optic nerve neurodegeneration, there is an unmet need to focus on therapies for slowing down this process.7-9,17-22
This is important for patients first detected with moderate/advanced damage and already have a low reserve of RGC. Even after adequate treatment, there is a downward slope of age-related progression, which may cause visual disability in their lifetime. Hence, a key question emerges—can antiaging therapies and lifestyle modifications reduce the rate of age-related decline of RGC/RNFL in glaucoma patients? Therapeutic strategies that may reverse or retard aging, will not decrease the incidence and morbidity due to age-related chronic diseases, but also prolong the healthy lifespan, improving the quality of life of the individual. In this article, we will briefly discuss the pathophysiology of age-related changes; the potential role, and new strategies to reverse, or at least, slow aging.
HOW DOES AGING IMPACT GLAUCOMA PATIENTS?
Aging and Ocular Stiffness
With advancing age, there are alterations in extracellular matrix (ECM) microstructure like increased ECM deposition, assembly, and subsequent crosslinking, leading to increased tissue stiffness.23,24 It has been shown that ocular rigidity increases with increasing age.25 There is age-related thickening or increased stiffness of trabecular meshwork (TM) and Schlemm’s canal (SC) cells and tissues, leading to elevated IOP.26
In glaucoma, the lamina cribrosa of the optic nerve head is the principal site of RGC axonal damage. During aging, due to the accumulation of advanced glycation end products, profound changes are observed in the collagenous and noncollagenous components of ECM of lamina cribrosa causing stiffening and reduced compliance at the optic nerve head, leading to increased susceptibility to IOP-induced damage.27 Like lamina cribrosa, age-related alterations in ECM of sclera and peripapillary sclera (thinning, stiffening) also have a significant impact on the biomechanics of optic nerve head.28 Stiff sclera causes decreased optic canal expansion and increases ganglion cell loss.29,30 Age-related structural changes may lead to a reduction of corneal hysteresis (a measure of the change in viscoelastic damping of the cornea) and corneal resistance factor.31 Lower corneal hysteresis is associated with an increased risk for glaucoma progression.
Aging and Retinal Ganglion Cell Loss
Aging is known to be associated with the loss of RGC and their axons.32,33 With increasing age, the proportion of neuronal tissue in the RNFL also decreases.33
In older age, the mechanical risk factors associated with retinal ganglion cell loss include a stiff sclera and decreased optic canal expansion.30 Apart from these mechanical factors, age-related biochemical alterations contribute to retinal ganglion cell loss. Most of these biochemical alterations are mediated by caspase-dependent apoptosis, histone lysine methylation, and histone acetylase (HAT)/histone deacetylase (HDAC) deacetylation.34-36 Nuclear factor (erythroid-derived 2)- like 2 (NRF2), a transcription factor that regulates cellular redox homeostasis, declines with age.37 Age-related alterations in redox homeostasis prevent reactive oxygen species (ROS) reduction. The increased ROS causes oxidative stress, damages mitochondrial deoxyribonucleic acid (DNA), and increases the optic nerve’s neurodegenerative vulnerability.37-39
WHY DO WE AGE—PATHOPHYSIOLOGY OF AGING
Aging occurs mainly due to cumulative DNA damage and epigenetic dysregulation. The epigenome determines which genes are switched on (functional) or off (not functional), and this gets dysregulated as we age, leading to cell damage. There is a shortening of telomeres that caps and protects the DNA in our chromosomes. There is also an accumulation of protein due to loss of protein homeostasis related to this, an increase in crosslinked proteins that bind to each other—advanced glycation crosslinks and an increase in senescent cells which are harmful to healthy cells. There is a loss of energy production with a reduction in mitochondrial function and a loss of stem cells, which are responsible for cell rejuvenation or tissue repair. Chronic, low-grade inflammation, also called inflammaging, involves both cytokine and noncytokine mediate processes, and is central to immunosenescence.
There is also considerable evidence that lifestyle factors are the triggers for systemic physiological imbalances. The latter is a result of the underlying oxidative stress, insulin resistance, and hyperinsulinemia,7 imbalances in the renin–angiotensin–aldosterone system, as well as autonomic and immunomodulatory dysregulation. In fact, insulin resistance has been shown to have a positive correlation with IOP, and the former, along with hyperinsulinemia may, thus, contribute to glaucoma. The interaction between the lifestyle style triggers and their resultant physiological malfunctions and individual genetic susceptibility is known to influence not only aging, but also several age-related diseases.2,7-9
Stress and Aging
With increasing age, there is a shortening of telomeres; thus, telomere length is a marker of cellular aging. Psychological stress can be associated with decreased telomere length.40 Darrow et al., in their meta-analysis, reported that there is a shortening of telomere length in patients with psychiatric disorders (like depression, anxiety, posttraumatic stress disorder, etc.) compared to controls.41 The underlying mechanisms for the association of chronic psychological stress and shorter telomere are poorly understood. During stressful events, the hypothalamic–pituitary–adrenal axis (HPA) is activated, causing a rapid (but transient) increase in glucocorticoid stress hormone.42 There may be an increase in oxidative stress if repeated activation of the HPA axis occurs. The oxidizing molecule can affect telomeres, which leads to the hypothesis that increased glucocorticoids cause telomere shortening. Steptoe et al. reported that cortisol responsivity may partly mediate the relationship between psychological stress and cellular aging.43 Jiang et al.’s meta-analysis also supported a relationship between cortisol reactivity and telomere shortening.44 Animal experimental studies also suggested that exposure to chronic stress and glucocorticoids is associated with shortened telomeres, which may be partially reversible.45 People who are exposed to chronic stress age rapidly due to telomere shortening.46
Antiaging Therapy
While aging, an organism experiences a series of progressively degenerative changes and becomes more sensitive to internal and external stimuli which leads to an aggravation of oxidative stress, accumulation of inflammation, apoptosis of cells, damage to structures and functions of cells/organs, and finally death.47,48 There are some interventions in animal models or even in human studies that are known to have antiaging properties and can increase the lifespan.49 Activation of the sirtuin can be a useful method for lifespan extension.50 Quercetin can regulate the inflammatory response, oxidative stress, mitochondrial dysfunction, autophagy, and apoptosis by activating sirtuin 1 in aging-related diseases.51-53 Many studies have shown that resveratrol has antiaging properties, can extend the lifespan, and also treat age-related diseases.54-61 The mechanisms by which resveratrol causes antiaging effects include suppression of oxidative stress, inhibition of inflammation, improvement of mitochondrial function, and regulation of apoptosis.62 In recent years, the role of hyperbaric oxygen therapy (HBOT–delivering 100% oxygen at atmospheric pressure) in antiaging therapy has been explored.63-65 HBOT alters gene expression, delays cell senescence, assists in telomere length enhancement, and thus has the potential for regenerative and antiaging therapy.64 Thus, vitamin D can act as a shield against aging. Due to the critical effect exerted by vitamin D, it can be considered a tool to tackle immunosenescence, oxi-inflammaging, and whole-body aging. However, there are significant limitations to translating knowledge into clinical practice.66 Oleic acid, coenzyme Q10, alpha-lipoic acid, and nicotinamide mononucleotide (NMN) supplementation are gaining attention for antiaging therapy. Further studies must assess their potential benefit and safety.67-72 NMN as a sirtuin-activating agent had protective effects against age-related ocular diseases such as dry eye, glaucoma, and macular degeneration.73 Similarly, many strategies were tried to protect or regenerate the RGC Cells.11,74-76 Skoufis and Segos reported that antiaging therapy could aid in glaucoma control, improving the ocular microcirculation.77
Epigenetic Reprogramming
It is proposed that during aging, the accumulation of epigenetic noise/loss of epigenetic information disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity.78-80 Even though aging is thought to be a unidirectional process, there are some situations in which biological age can be reset entirely, such as in “immortal” jellyfish and when cloning an animal using nuclear transfer. If the mammalian cells had preserved a faithful copy of epigenetic information from an earlier stage of life, it might be possible to reverse aging by using that information.81 Sinclair stated that restoring epigenetic information to reverse aging is similar to rebooting a malfunctioning computer.
Epigenetic reprogramming is the key to reversing aging and increasing longevity.82 The epigenetic rejuvenation is achieved through transcription factor-mediated reprogramming or pharmacological interventions based on small molecules, like DNA methyltransferase inhibitors and HDAC inhibitors.
Transcription Factor-mediated Reprogramming
Almost all species have a decline in regenerative potential during aging. In mammals, the central nervous system (CNS) is among the first to lose regenerative potential.83,84 RGC (part of CNS) can regenerate axons after damage during the embryonic or neonatal period, but this capacity is lost within days after birth.83,85 The trio of genes Oct4, Sox2, and Klf4 (together named OSK), which are active in stem cells, can help to rewind the adult cells to an earlier state. Lu et al. showed that ectopic expression of OSK in mouse RGC can restore youthful DNA methylation patterns and transcriptomes, promote axon regeneration after injury, and reverse vision in mouse models of glaucoma and aged mice.76 The DNA demethylases TET1 and TET2 are required for the beneficial effects of OSK-induced reprogramming in axon regeneration and vision restoration. It is a partial reprogramming that enables the epigenetic landscape of cells and DNA methylation patterns to be reset, allowing cells to rejuvenate and tissues to regenerate without reaching a pluripotency state, thus minimizing the risk of tumorigenesis.86
Deoxyribonucleic Acid Methyltransferase Inhibitors-mediated Reprogramming
With increasing age, there are alterations in DNA methylation like global hypomethylation and site-specific hypermethylation, which are linked to many age-related diseases like diabetes, cancer, cardiovascular diseases, neurodegenerative disorders, etc.87 DNA methylation is catalyzed by DNA methyltransferases.88 So, targeting DNA methyltransferases with specific inhibitors to delay or reverse the pathologies can be a potential antiaging strategy. FDA had approved DNA methyltransferase inhibitors like 5-azacitidine and decitabine as antitumor agents.89,90 There is limited experimental evidence regarding the direct effects of DNA methyltransferase inhibitors on age-related diseases.
Histone Deacetylase Inhibitors-mediated Reprogramming
With increasing age, there are changes in histone acetylation, particularly alterations in specific histone marks and the expression of HDACs.91 The opposing actions of histone acetyltransferases (HATs) and HDACs (whose activities are correlated with gene activation and gene silencing, respectively) control the acetylation of core histones.92 HDAC inhibitors target epigenetic changes and, indirectly, the remaining hallmarks of aging and thus have shown promise in treating age-related chronic disorders.93 HDAC inhibitors reprogram chromatin through modulating p53, p300/CREB binding protein, p300/CBP-associated factor and thus promoting neuroprotection.33,94,95 HDAC inhibitors like RGFP966 or conditional knockout of the Hdac3 gene (encodes HDAC3), offer protection to the RGC.74,75
Current Challenges in Epigenetic Reprogramming
Epigenetic reprogramming can reverse aging and increase longevity, but several challenges hinder these strategies. Despite progress, there is an incomplete understanding of the intricate processes regulating gene expression and cellular reprogramming.96 After attaining youthful characteristics, sustaining them and preventing their reversion to an aged state over extended periods is complex and requires continuous monitoring and optimization of reprogramming. Delivery of transcription factors for reprogramming by the viral vectors can lead to pathological insertional mutagenesis and reactivation of reprogramming factors.97 Reprogramming factors like OSKM genes may be associated with the risk of neoplastic development in reprogrammed cells.98 Most of these reprogramming has been successful only in rejuvenating animal tissues. New technologies and further research are needed to apply these findings in humans.
Lifestyle Modifications for Antiaging
Several lifestyle factors like physical activity, smoking, drinking, nutrition, sleep, stress, etc. can be associated with age-related diseases and death. Lifestyle modifications can be beneficial to prevent aging and age-related diseases. Most of these aim at reducing the allostatic overload which results in physiological dysregulation due to chronic stress.2,7-9,99-129
Stress Management
Meditation-based interventions have been shown to reduce stress and improve general health.101,102 Our previous studies have shown that meditation-based interventions can also reduce stress and improve the quality of life in patients with glaucoma. A recent meta-analysis by Schutte et al. suggested that meditation-based interventions may prevent telomere attrition or increase telomere length.106 In long-term meditators, telomere length correlates with DNA methylation.107 Tolahunase et al. studied the impact of yoga and meditation-based lifestyle intervention (YMLI) on cellular aging in apparently healthy individuals.108 In their study, a 12-week course of YMLI significantly reduced the mean levels of 8-hydroxy-2’-deoxyguanosine, ROS, cortisol, and IL-6. It also significantly increased the mean levels of total antioxidant capacity, telomerase activity, β-endorphin, BDNF, and sirtuin-1. The mean level of telomere length was increased (but the finding was not significant p = 0.069). They concluded that YMLI can reduce the rate of cellular aging. Similarly, Dasanayaka et al. studied the associations of meditation with telomere dynamics in healthy adults and reported that meditation has multilevel benefits in telomere dynamics (compared to nonmeditators, meditators had longer relative telomere length, higher relative expression of hTERT and hTR genes and significantly lower methylation level of the promoter region of hTERT gene) with potential to promote healthy aging.109 Thus, meditation can aid in healthy aging by appropriate telomere dynamics.110-112
Avoid Smoking and Alcohol Consumption
Cigarette smoking is an important accelerator of the aging process both directly (complex mechanisms mediated by excessive free radical formation) and indirectly (by favoring the appearance of various pathologies).113,114 Smokers have a significantly higher biological age than chronological age and a higher percentage of fat tissue than nonsmokers.115 Nonsmokers can delay the aging process and the appearance of diseases. Chronic alcohol consumption accelerates and exacerbates the age-related diseases.116 Alcohol consumption can increase oxidative stress and inflammation, influencing telomere length.117 Wang et al. reported that the long-term average alcohol consumption is associated with acceleration of biological age.118 Thus, avoiding smoking and alcohol consumption will aid in healthy aging.
Improving Physical Activity
Physical activity/regular exercise can limit the prevalence of various cardiometabolic and neurodegenerative diseases by reducing mitochondrial dysfunction.119 It prevents the decline in mitochondrial respiration, mitigates aging-related loss of muscle mass, and enhances insulin sensitivity.120 It can maintain blood pressure, control blood sugar and body weight, reduce dyslipidemia, and improve bone and muscle health. Thus, exercise/physical activity can promote healthy aging.
Diet Modification
Appropriate nutrition intake is crucial to prevent or delay the development of diseases, boost longevity, and promote healthy aging.121,122 One should consume diets rich in vegetables, fruits, nuts, cereals, fish, unsaturated fats, antioxidants, potassium, and omega-3, choose a low carbohydrate diet, reduce intake of red meat, and ultraprocessed foods. Calorie restriction has also been shown to improve lifespans in some model organisms.123 It works by neutralizing the harmful effects of ROS and oxidative damage.124
Sleep Quality and Quantity
Sleep is integral to the health of metabolic and physiological systems, endocrine function, immune response, and retardation of senescence. Poor sleep is known to accelerate aging, and age-related diseases, like Alzheimer’s disease, hematopoietic stem cell dysfunction, and coronary artery disease.125-131 Numerous studies have reported that improving the quantity and quality of sleep can be considered as an antiaging treatment that can prevent, slow, or even. Similarly, the chronobiological effects of melatonin include a reversal of the cellular degeneration associated with aging. Melatonin, and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), have neuroprotective, anti-inflammatory, immunomodulatory, and oncostatic properties.125-130
Increased HIF-1α protein levels, higher oxidative stress markers 8-OHdG and TNF-α, and a decrease in pyruvate dehydrogenase kinase-1 protein were noted in rats with chronic intermittent hypoxia, induced by obstructive sleep apnea-like models. These are like the oxidative stress, inflammation, and upregulation of HIF-1α in the retina, seen in early-stage glaucoma.129 Obstructive Sleep Apnea (OSA), however, appears to be an aggravating factor, rather than an independent risk factor for glaucoma, even though there is a significant association between OSA, glaucoma, and higher eye pressures.130,131
CONCLUSION
To conclude, aging can cause or accelerate the loss of RGC either by mechanical or biochemical alterations. Several research studies have attempted to stop or reverse aging and age-related diseases, with promising results. However, there are several challenges to using them in clinical practice at the present time. Future research could provide a valuable intervention to halt or reverse age-related loss of RGC and be a helpful armamentarium in treating glaucoma. At present, lifestyle modifications could be considered as adjuvant therapy in glaucoma patients, with an aim to evaluate and reduce the allostatic load, to restore the physiological balance.9 That these may also have a potentially beneficial or protective effect on other age-related noncommunicable diseases is an added advantage. It is important to establish a new target in glaucoma patients other than the target IOP for “reversing aging” or “slowing the aging process” to mitigate the age-related retinal ganglion cell loss. An interesting research question for the future would be to evaluate glaucoma “fast progressors” for “accelerated aging” and evaluate if lifestyle interventions can slow/reverse both.
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