Meibomian glands (MGs) are located within the tarsal plate of the eyelid and secrete meibum onto the ocular surface [1]. Meibum is a lipid-rich secretion that is necessary for stabilizing the tear film and for protecting the ocular surface from various hazardous factors. Changes in the quality and quantity of meibum cause an increase in tear film evaporation, leading to evaporative dry eye disease (EDED) affecting approximately 21 million individuals in the US, with these numbers increasing with the aging population [2]. The prevalence of dry eye disease (DED) worldwide ranges from 5 to 50 %, depending on different populations [[2], [3], [4]]. Studies have shown that DED has multiple etiologies, with Meibomian gland dysfunction (MGD) being the leading cause [3,5]. In fact, clinical studies suggest ∼85 % of all DED cases are caused by some form of MGD [6]. MGD is an underdiagnosed disease, and it is estimated that, in the US, approximately 70 % of the population over 60 have MGD [7]. Moreover, MGD is believed to be more prevalent in the Asian populations compared to Caucasians [8]. Symptoms associated with dry eye include burning sensation, itchy eyes, pain, fatigued and/or sore eyes, dryness sensation, red eyes, photophobia and blurred vision, all of which decrease productivity and reduce the quality of life [9]. With age, MGs undergo various age-related changes, including decreased acinar basal cell proliferation, MG atrophy, and eventual MG drop-out, leading to age-related MGD (ARMGD) [10,11]. Unfortunately, little is known about what causes these changes to the MG, making developing therapies difficult. Conventionally, ARMGD is believed to be caused by obstruction of the MG secretory duct, leading to stasis of the meibum within the duct, which, in turn, leads to backpressure within the gland triggering MG atrophy [12]. Hyperkeratinization at the opening of the collecting duct that occurs with aging has been regarded as a major cause of MG obstruction [13]. More recently it was proposed that a decrease in cell proliferation within the basal layer of the MG leads to reduced meibocyte differentiation, and, consequently, leads to MG atrophy and reduced meibum production, all culminating in ARMGD [14]. Other studies have speculated that, as with the lacrimal gland [15,16], the MG could suffer inflammatory cell infiltration with age that could contribute towards ARMGD [17,18]. More recently, studies have suggested that a loss in the number of MG progenitor cells over time could contribute towards ARMGD [14]. Additionally, some studies have speculated that changes in MG innervation patterns could also contribute towards ARMGD [19]. Finally, the eyelids also change drastically with aging, with a notable loss of elasticity and sagging. It has been speculated that changes in the biomechanical properties of the tarsal plate and overall eyelids could also contribute to ARMGD. Unfortunately, when studying naturally occurring ARMGD, it is impossible to separate each of these factors in order to understand their individual contributions to MG atrophy and eventual drop out (see Fig. 1).

Although the pathophysiology of ARMGD remains poorly understood, there are many well-defined risk factors. The primary risk factor for MGD reported to date is aging [1]. Other risk factors include hormonal imbalances, diet, eyelid defects, prolonged contact lens wear, excessive use of make-up, eyelid tattooing, and Demodex folliculorum infestation [20,21]. Certain systemic conditions can place individuals at a higher risk of developing MGD, such as, autoimmune diseases such as Sjögren's syndrome, rosacea, lupus, psoriasis, and rheumatoid arthritis, and, Stevens-Johnson Syndrome (SJS), and hypertension [22,23]. Importantly, some lifestyle changes can help to slow the progression of MGD, for example dietary changes by increasing the ingestion of foods containing omega-3 fatty acids and practicing good eyelid hygiene [22].

Aging is a complex process that affects all cells and tissues of the human body. Traditionally, the hallmarks of aging were considered to be 1. genomic instability which results in DNA mutations, 2. telomere attrition leading to telomere shortening, 3) epigenetic alterations, 4. loss of proteostasis leading to the accumulation of misfolded proteins, 5) deregulated nutrient sensing, 6) mitochondrial dysfunction, 7) cellular senescence, 8) stem cell exhaustion, and 9) altered intercellular communication [24]. These changes that occur with aging all lead to an accumulation of damage to cells and tissues, which is aggravated by a decrease in the ability to repair damages that also occurs with aging. Therefore, it is not surprising that aging is a major risk factor in most diseases, including ARMGD. Herein, this review covers how the aging process affects the MG, and more importantly, how age-related changes to the MG cause MG atrophy and MG drop-out, ultimately leading to ARMGD.