Despite the many comorbidities associated with increased risk of severe acute respiratory syndrome, age remains the greatest risk factor for COVID-19 mortality and is a significant risk for long COVID.

Declared a global pandemic by the WHO on 11 March 2020, COVID-19 has more than 245 million people worldwide; nearly 5 million deaths linked to infection with SARS-CoV-2, the causative agent of the disease, have been reported globally. A new Nature Aging review presents the aging immune system, its ability to respond to SARS-CoV-2 and possible interventions that could enhance immune function.

Longevity.Technology: When we are exposed to a pathogen infection, our immune system engages the intruder in two steps. The innate, non-specific, immune system reacts immediately by eliminating infected cells. The adaptive immune system or acquired immunity – specific to a pathogen – is responsible for generating antibodies that bolster our immune response. With aging, these systems wane and leave us more vulnerable in the face of new infections. Add into a mix recent studies that show that older people are more likely to develop long COVID, and the need for effective interventions to bolster immunity or immune response is clear.

Severe outcomes of SARS-CoV-2 infection are likely to result from a “pathological hyperinflammatory response initiating uncontrolled local tissue damage, vascular leakage, systemic cytokine storm and thrombosis”, write the authors of the review [1]. Add the age risk factor and you’re likely to be more vulnerable to these outcomes.

The destructive inflammatory response is seen in the high levels of cytokines and chemokines – inflammatory mediators – of patients with severe COVID-19 [1]. They contribute to the risk for critical outcomes of the disease such as acute respiratory distress syndrome [2] or coagulopathy [3].

Many of the substantially elevated cytokines found in severe cases of COVID-19 tend to be elevated basally in older adults as a result from inflammaging – age-dependent chronic inflammation that makes immune cells hyporesponsive. One of these is interleukin 6 (IL-6), a stable indicator of poor COVID-19 outcomes [1] and one of the most reliable aging parameters. IL-6 engenders neutrophilia – an increase of neutrophils, the most abundant white blood cells type – another indicator of poor clinical outcomes of COVID-19 [4].

SARS-CoV-2 infection, inflammaging, and the uncontrolled inflammatory response led to an exaggerated innate and adaptive immune response, the facilitation of viral replication and worsened COVID-19 outcomes [1].

Dysregulated innate response

ACE2 expression – the primary cell receptor of SARS-CoV-2 that converts inflammatory mediators such as Angiotensin II into anti-inflammatory ones – was diminished in older adults, and levels of Angiotensin II were elevated in severe cases of COVID-19. SARS-CoV-2 was thus less likely to infect cells, but the risk for an exacerbated pro-inflammatory response was heightened [1].

Low levels of type 1 interferons (IFNs) – responsible for the activation of macrophages and T cell responses – were associated with severe cases of COVID-19 [5]. Moreover, aging leads to a delayed type 1 IFNs response, thus an impaired adaptive immune response [1].

Poor adaptive response

Aging diminishes the diversity of naïve T and B cells polyclonal repertoire. Combined with an increased exhaustion of functional T cells and a loss of B cells potential to create neutralising antibodies, viral clearance can be compromised [1].

Poor adaptive response to SARS-CoV-2 infection in the elderly is driven by multiple characteristics of immunosenescence. Severe COVID-19 outcomes have been associated with lower T cell diversity, T cell exhaustion and lymphopenia – reduction of T cells in the blood – with patients over 60 having the lowest total number of T cells in their blood [6]. Inefficient pre-existing immunity – acquired from prior coronavirus infections – and faulty B cell maturation contribute to one’s progression to a severe state [1].

Possible interventions?

The development of therapeutics that can enhance our health span is an area of research from which we can benefit to improve our immune system, the first line of defence against any infection.

Metformin is a strategy that has already been shown to reduce the epigenetic age by 1.5 years. The authors write about two recent studies showing that metformin could also lower the risk of severe COVID-19 [1].

Rapamycin and rapalogs can extend lifespan through their immunostimulatory effect when administrated at low doses. While rapamycin could protect the elderly from COVID-19 the review warrants for proper investigations, as rapamycin tends to enhance the expression of IL-6, associated with poor disease outcomes [1].

Senolytics – for the ability to reduce pro-inflammatory effects – NAD boosting – for improving mitochondrial function, essential in immune cells to contain viral propagation – or calorie restriction – shown to reverse the age-related upregulation of inflammatory genes – are possible options. Whether any of these could work in the context of SARS-CoV-2 infection also warrants more research [1].

To where?

The delay in early immune responses seen in the elderly can quickly lead to a ‘tipping point’ where the storm of pro-inflammatory cytokines, the tissue destruction and vascular permeability propagate uncontrollably, and lead to the enhanced morbidity of severe COVID-19 [1].

Further human studies are necessary as the extrapolation of results from mouse to human model requires caution since the two species’ immune systems are not quite alike. An aged immune system is clearly the main risk factor for poor outcomes of COVID-19. However, more research is needed to clarify the mechanisms and interactions between the immunosenescent characteristics of the disease and the contribution of age-related immune system dysfunctions [1].

Further research to determine the lasting imprint of both SARS-CoV-2 infection and Long COVID on human physiology is also needed. Finally, the successes of the COVID-19 vaccines are promising, but longitudinal studies are required to determine their sustained efficacy.

[1] https://www.nature.com/articles/s43587-021-00114-7
[2] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
[3] https://www.mdpi.com/2077-0383/8/5/728
[4] https://pubmed.ncbi.nlm.nih.gov/32283162/
[5] https://www.science.org/doi/10.1126/science.abc6027
[6] https://www.frontiersin.org/articles/10.3389/fimmu.2020.00827/full

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