New study spotlights therapeutic solution for long COVID fatigue.

AgelessRx researchers suggest LDN and NAD+ not only address long COVID symptoms, but target the root cause of its pathology.

A recent trial suggested that combining NAD+ with Low Dose Naltrexone (LDN) could improve fatigue symptoms and quality of life in patients with persistent fatigue after COVID-19 – also known as long COVID [1]. These results not only signify progress in combating long COVID but also represent an important step in addressing the underlying causes of the debilitating condition which is currently affecting nearly 18 million people living in the US [2].

Longevity.Technology: Long COVID, with its array of symptoms resembling accelerated aging, presents a formidable challenge. From fatigue to cognitive decline, the parallels are evident, and studies have shown that the biological aging process is accelerated during COVID infection [3], persisting in individuals with long COVID [4]. It is evident that novel therapeutic interventions are needed.

Both NAD+ and LDN are recognized as gerotherapeutic treatments, targeting core biological processes that underpin the aging process. AgelessRx’s study sheds light on a promising avenue for addressing long COVID fatigue, which has proven resistant to conventional treatments. Through a 12-week regimen combining LDN and NAD+ patches, participants experienced tangible improvements across various metrics of quality of life, noting significant improvements in pain, emotional wellbeing, daily role limitations, and energy levels. Notably, over half of the participants (52%) reported a substantial 20% or more enhancement in their overall well-being [1]. We sat down with Dr Sajad Zalzala, AgelessRx’s Co-founder and Chief Medical Officer, and Girish Harinath, Senior Research Manager, to find out more.

In terms of impacting healthspan and longevity, long COVID and other post-viral syndromes present a significant concern, says Zalzala, who adds that these conditions can lead to prolonged illness, reduced quality of life and a range of chronic health issues. 

“The inflammatory and immune dysfunction observed in Long-COVID are linked to hallmarks of aging, especially considering the concepts of immunosenescence and inflammaging,” he says. 

Immunosenescence refers to the gradual decline in immune function brought on by natural aging, while inflammaging is characterized by the chronic, low-grade inflammation often observed in older individuals. 

“These phenomena can exacerbate the effects of COVID-19 and contribute to the severity of Long-COVID symptoms,” Zalzala explains. “The intertwined processes of immunosenescence and inflammaging, characterized by a decline in immune system efficacy and persistent low-level inflammation, respectively, are collectively implicated in accelerating the aging process. This accelerated aging is not merely a byproduct of chronological aging; rather, it’s a complex interaction of biological processes that can prematurely wear down the body’s systems, akin to the wear and tear on machinery that hasn’t been regularly maintained.”

This means that when it comes to long COVID, these phenomena may exacerbate the condition’s impact, contributing to a faster decline in physiological resilience and health, which mirrors aging but occurs more rapidly than the normal aging process.

Harinath adds that research has highlighted that older individuals may have an inappropriate immune response to SARS-CoV-2 infection due to immunosenescence, and this can lead to an inability to launch a robust antiviral response and control viral replication efficiently [1]. 

“In addition, the accumulation of senescent immune cells, which produce excessive amounts of inflammatory cytokines, contributes to the heightened state of inflammation seen in older COVID-19 patients. This excessive inflammation can further damage tissues and impair the function of the immune system, potentially exacerbating the symptoms of Long-COVID and influencing its severity.”

Harinath references a study linking long COVID symptoms directly to inflammation, demonstrating that prolonged inflammation following a SARS-CoV-2 infection can cause lasting damage to organs such as the lungs and kidneys, affect the brain and correlate with behavioral changes [5]. 

“This inflammation persists well beyond the acute phase of the infection, suggesting that the ongoing inflammatory response plays a crucial role in the manifestation of Long-COVID symptoms,” he explains. 

The recent study explored the impact of NAD+ and LDN on long COVID; both are gerotherapeutic candidates that have been shown to target fundamental processes that drive the biology of aging. 

“Low dose Naltrexone demonstrates evidence for targeting 9 hallmarks of aging – especially inflammation, senescence, and mitochondrial dysfunction,” Zalzala explains. “LDN has been shown to help ‘balance’ the immune system and makes it less reactive and less likely to damage our own cells/organs (known as an autoimmune response). One of the hallmarks of Long-COVID is an impaired immune system that becomes more reactive (fanning the flames of chronic inflammation and harming our own tissues and cells) and less precise (at eliminating pathogens).”

Zalzala adds that NAD+ is essential for maintaining mitochondrial health and functionality and should be considered an essential “longevity micronutrient” as it plays a crucial role in thousands of different chemical reactions, declines with age and is necessary for repair of several different types of damages. 

“NAD+ supports built-in quality control systems in the form of enzymes and proteins that repair damage and resolve dysfunction,” he explains. “There are implications within the literature that Long-COVID impairs mitochondrial function and cellular metabolism resulting in compromised energy production and loss of homeostasis: the ability for the cells, tissues, and organs of the body to maintain healthy physiological function in response to various stressors.”

There may also be synergy at play, as the combination of NAD+ and LDN could be synergizing to address root causes that drive long-COVID pathology helping to restore health as reflected by significant improvements in quality of life and fatigue.

“Both LDN and NAD+ have gathered evidence to be proposed as potential gerotherapeutic candidates,targeting and remedying certain hallmarks of the fundamental biology of aging leading to improved age-related outcomes,” explains Harinath. “NAD+ has gathered quite a bit more support from the longevity field. However, we propose LDN be considered a novel gerotherapeutic candidate as it has demonstrated wide ranging benefits on specific diseases as well as age-related outcomes and is gathering mechanistic evidence for targeting the hallmarks of aging.”

Zalzala and Harinath hope the study will inspire others to follow up on this promising combinatorial intervention for the treatment of individuals with long COVID. 

“We’d like to see a larger placebo controlled study exploring benefits on quality of life, but also examining objective biomarkers like plasma inflammatory factors, metrics of heart function, cognitive assays, and even biomarkers of aging,” explains Harinath, adding that AgelessRx currently has a large, ongoing clinical study with LDN evaluating its effects on various healthspan metrics including Quality of Life and immune health status. 

“We plan to publish those findings soon, highlighting the promise of LDN for addressing multiple aspects of health and functioning in a normative aging population.”

Zalzala says if long COVID can be mitigated, then there should be reasons to be very optimistic about doing the same with general aging.

“The insights gained from studying the immune and inflammatory aspects of Long-COVID, particularly their links to accelerated aging processes like immunosenescence and inflammaging, have profound implications for the broader field of medicine, especially in the management and understanding of chronic health conditions,” he explains. “These findings underscore the interconnectedness of immune dysfunction, chronic inflammation, and chronic disease progression, highlighting several key areas for potential impact.”

Research on long COVID’s link to accelerated aging processes such as immunosenescence and inflammaging could profoundly influence the development of future treatments for long COVID and related conditions, as Zalzala explains. 

“By pinpointing specific immune and hormonal imbalances, this research paves the way for targeted therapies aimed at modulating the immune system and reducing inflammation, potentially reversing accelerated aging effects.

“Furthermore, the identification of biomarkers for Long-COVID could lead to early detection and personalized treatment strategies for other conditions associated with accelerated aging, and understanding the triggers of chronic inflammation could facilitate preventive measures to delay the onset of such conditions, heralding a shift towards more personalized, preventative, and precise approaches in medicine.”

[1] https://www.sciencedirect.com/science/article/pii/S2666354624000115[2] https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm[3] https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2022.1034227/full[4] https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00263-8/fulltext[5] https://www.nih.gov/news-events/nih-research-matters/long-covid-symptoms-linked-inflammation