A meta-analysis of 91 studies of about 400,000 people showed a 13% increased morality risk
among people with low compare to high contact frequency [53]. Another meta-analysis of 148
prospective studies (308,849 participants) found that poor social relationships was associated
with 50% increased mortality risk. People who were socially isolated or fell lonely had 45% and
40% increased mortality risk, respectively. These findings were consistent across ages, sex,
initial health status, cause of death and follow-up periods [52]. Importantly, the increased risk for
mortality was found comparable to smoking and exceeding well-established risk factors such as
obesity and physical inactivity [52]. An umbrella review of 40 systematic reviews including 10
meta-analyses demonstrated that compromised social relationships were associated with
increased risk of all-cause mortality, depression, anxiety suicide, cancer and overall physical
illness [51].
As described earlier, wearing facemasks causing hypoxic and hypercapnic state that constantly
challenges the normal homeostasis, and activates “fight or flight” stress response, an important
survival mechanism in the human body [11], [12], [13]. The acute stress response includes
activation of nervous, endocrine, cardiovascular, and the immune systems [47], [54], [55], [56].
These include activation of the limbic part of the brain, release stress hormones (adrenalin,
neuro-adrenalin and cortisol), changes in blood flow distribution (vasodilation of peripheral blood
vessels and vasoconstriction of visceral blood vessels) and activation of the immune system
response (secretion of macrophages and natural killer cells) [47], [48]. Encountering people who
wearing facemasks activates innate stress-fear emotion, which is fundamental to all humans in
danger or life threating situations, such as death or unknown, unpredictable outcome. While
acute stress response (seconds to minutes) is adaptive reaction to challenges and part of the
survival mechanism, chronic and prolonged state of stress-fear is maladaptive and has
detrimental effects on physical and mental health. The repeatedly or continuously activated
stress-fear response causes the body to operate on survival mode, having sustain increase in
blood pressure, pro-inflammatory state and immunosuppression [47], [48].

Long-Term health consequences of wearing facemasks
Long-term practice of wearing facemasks has strong potential for devastating health
consequences. Prolonged hypoxic-hypercapnic state compromises normal physiological and
psychological balance, deteriorating health and promotes the developing and progression of
existing chronic diseases [23], [38], [39], [43], [47], [48], [57], [11], [12], [13]. For instance,
ischemic heart disease caused by hypoxic damage to the myocardium is the most common
form of cardiovascular disease and is a number one cause of death worldwide (44% of all noncommunicable diseases) with 17.9 million deaths occurred in 2016 [57]. Hypoxia also playing an
important role in cancer burden [58]. Cellular hypoxia has strong mechanistic feature in
promoting cancer initiation, progression, metastasis, predicting clinical outcomes and usually
presents a poorer survival in patients with cancer. Most solid tumors present some degree of
hypoxia, which is independent predictor of more aggressive disease, resistance to cancer
therapies and poorer clinical outcomes [59], [60]. Worth note, cancer is one of the leading
causes of death worldwide, with an estimate of more than 18 million new diagnosed cases and
9.6 million cancer-related deaths occurred in 2018 [61].
With respect to mental health, global estimates showing that COVID-19 will cause a catastrophe
due to collateral psychological damage such as quarantine, lockdowns, unemployment,
economic collapse, social isolation, violence and suicides [62], [63], [64]. Chronic stress along
with hypoxic and hypercapnic conditions knocks the body out of balance, and can cause
headaches, fatigue, stomach issues, muscle tension, mood disturbances, insomnia and
accelerated aging [47], [48], [65], [66], [67]. This state suppressing the immune system to
protect the body from viruses and bacteria, decreasing cognitive function, promoting the
developing and exacerbating the major health issues including hypertension, cardiovascular
disease, diabetes, cancer, Alzheimer disease, rising anxiety and depression states, causes
social isolation and loneliness and increasing the risk for prematurely mortality [47], [48], [51],
[56], [66].

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