Our research team at the University of Palermo, actively studying Sicilian centenarians, was impressed by a study conducted in Belgium by Professor Poulain's group. The Belgian researchers analysed the mortality patterns based on the birth year and month of Belgians who turned 100 during the 2020 COVID-19 pandemic. These individuals were born around the end of World War I and during the onset of the H1N1 "Spanish flu" pandemic. They found that older centenarians had significantly lower COVID-19 mortality rates compared to younger centenarians, with the most notable difference observed among those born closest to August 1, 1918, the date marking the onset of the Spanish flu pandemic in Belgium. This temporal coincidence between the Spanish flu epidemic and the birth of cohorts more vulnerable to COVID-19 in 2020 strongly suggested a link between exposure to the 1918 H1N1 pandemic influenza and resilience to SARS-CoV-2. The researchers hypothesized that cross-reactive immune mechanisms developed during the Spanish flu may have enabled centenarians to combat COVID-19 a century later.

Poulain et al.'s study did not explore gender differences or whether overall centenarian mortality increased like that of the broader older population. Motivated by these findings, we analysed mortality data of Sicilian centenarians from March 10, 2020 (the start of the pandemic in Italy), to December 31 of the same year, using 2019 as a control period. We observed excess mortality among centenarians, predominantly higher in men compared to women (33% versus 17%), a common trend in infectious diseases. Analysing by birth year (1918 cohorts), increased mortality was seen primarily in younger (<102 years) rather than older (>101 years) centenarians, aligning with Poulain's conclusions and extending our understanding. Therefore, the data on Sicilian centenarians confirm and extend Poulain et al.'s findings.

Intrigued by these insights, we conducted an extensive literature review confirming that, overall, centenarians did not exhibit greater resilience compared to other older individuals. Nonetheless, there are several anecdotal reports in literature of "older" female centenarians (> 101 years old) who contracted SARS-CoV-2 in 2020 or early 2021 and recovered spontaneously or with brief hospital stays.

We used our serum collection of 33 centenarians which include 7 semi-supercentenarians aged > 104 < 110 years, and 4 supercentenarians aged > 109 years, born between 1905 and 1922. These samples were collected before and after the peak of the COVID-19 pandemic in 2020. We conducted a retrospective serological study to explore how the Spanish Flu relates to COVID-19 and whether older centenarians showed resilience to COVID-19. To achieve this, we collaborated with researchers from Siena and Kent universities specialized  in COVID-19 and influenza serology.

Regarding the H1N1 virus of the Spanish flu, our study protocol aimed to produce the 1918 H1N1 pseudotype virus (PTV) and assess neutralizing antibodies against it. For COVID-19 serology, our study focused on detecting antibodies against the nucleocapsid protein (NP) of SARS-CoV-2. These antibodies indicate a past infection with the virus, which is particularly useful because mRNA vaccines do not generate an immune response against this specific protein. Additionally, we searched for neutralizing antibodies that specifically target the Spike protein of the virus. These antibodies are crucial as they are considered the best way to determine how well antibodies can protect against SARS-CoV-2 infection, whether someone was naturally infected or vaccinated..

 Medical history and laboratory results (anti NP positivity) suggest that 8 centenarians had been infected with SARS-CoV-2. The infection was mild or without symptoms, and none of them needed to be hospitalized, even though 3 of them were between 109 and 110 years old. The levels of anti-spike antibodies in the infected and/or vaccinated centenarians were higher, though not significantly, than those in a random sample of seventy-year-olds used as controls. All centenarians had antibody levels against the 1918 H1N1 PTV that were almost 50 times higher than those in the seventy-year-olds, showing the importance of long-lasting immune memory from over 100 years ago. Centenarians whose blood was collected before the COVID-19 pandemic had neutralizing antibodies against the 1918 H1N1 virus, but all tested negative for SARS-CoV-2.

This retrospective study shows that older centenarians are quite resilient to COVID-19, as they are capable of producing good levels of neutralizing antibodies and experienced mild or asymptomatic disease. This resilience might be linked to the 1918 Spanish flu pandemic, possibly through mechanisms like epigenetic changes rather than just cross-reactive antibodies between the 1918 H1N1 virus and SARS-CoV-2. Another possibility is that this resilience is simply due to their more advanced age, as studies from the Palermo University team have shown that older centenarians have better control over their immune-inflammatory responses compared to younger centenarians.

This study adds more evidence to the idea that controlling immune-inflammatory responses plays a significant role in achieving extreme longevity. However, this doesn't mean other organs and systems aren't also important. It's worth noting that the immune system has been studied more extensively and in-depth compared to other body systems and organs, mainly because it's easier to study outside of the body. Additionally, we should consider that an efficient immune system might be the result of a well-functioning body rather than the cause of it.