The most powerful tool to stop the acceleration of aging caused by mTOR dysfunction and cellular senescence.
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As immune function declines with age, a ripple effect ensues that accelerates aging. In an attempt to improve immune function, Dr. Joan Mannick's research has led her to examine the effect of mTOR inhibition on improving the aging immune system’s function. Mannick's trials have shown that the use of very low doses or intermittent doses of mTOR inhibitors actually enhances immune function. Despite this, the paradoxical nature of rapamycin's effects raises fascinating questions about the intricate relationship between immunity and aging. In this article, we explore the profound implications of Mannick's findings and delve deeper into the curious case of rapamycin—an immunosuppressant turned ally in enhancing immunity.
By: Daniel Tawfik
Rapidly growing evidence indicates that aging isn't simply a default outcome of our biological clocks winding down, but a process that can be regulated and altered, if we know which biological "switches" to flip. Scientists have observed that interfering with certain signaling pathways within our cells can delay aging and reduce aging-related characteristics across numerous species, even in mammals like us.
Prominently, the mTOR (mammalian target of rapamycin) pathway, a signaling route involved in regulating cell growth, has emerged as a key player in aging. Current research on rapamycin, a compound that inhibits the mTOR pathway, has shown notable effects in slowing the aging process.
We have previously discussed these benefits in the context of:
What is emerging from this research is a universal theory in which overactivity of the mTOR pathway acts as an accelerant of aging. In this context, mTOR inhibition through the use of rapamycin deaccelerates this process.
However, studying the impact of such interventions on human aging poses a significant challenge, given the long lifespan and the slow progression of aging-related conditions in humans.
To circumvent this issue, researcher Joan Mannick focused on a particular manifestation of aging that can be observed over a shorter time period: immunosenescence, or the decline in immune function that comes with old age.
Immunosenescence is a significant health concern, as it makes elderly people more susceptible to infections and less responsive to vaccines, such as those for influenza. In fact, adults over 65 account for a shocking 90% of flu-related deaths in the U.S., largely because their weakened immune systems have a reduced response to flu vaccines compared to younger adults.
This weakened immune response in the elderly stems from a range of issues, notably a reduction in the capacity of hematopoietic stem cells (HSCs)—which generate the body's blood cells—to produce naive lymphocytes, a type of white blood cell that plays a crucial role in our immune response. At the same time, there's an increase in the numbers of "exhausted" T lymphocytes, cells that have been worn out and have a diminished capacity to respond to foreign invaders.
The study built upon previous research showing that rapamycin extended the lifespan of mice and improved various aging-related conditions. In elderly mice, rapamycin treatment rejuvenated immune function, resulting in increased production of new lymphocytes, improved response to influenza vaccination, and even extended lifespan.
Mannick's study aimed to investigate whether rapamycin and its analog RAD001, another mTOR inhibitor, could replicate these positive effects in elderly humans. The results were very intriguing. RAD001 treatment appeared to ameliorate the age-related decline in immunological function in elderly volunteers, as evidenced by an enhanced response to influenza vaccination.
In Mannick's study, a total of 218 elderly participants aged 65 years and older were recruited from Australia and New Zealand for a randomized, observer-blind, placebo-controlled trial. They were administered one of three doses of RAD001, a variant of rapamycin: 0.5 mg daily, 5 mg weekly, or 20 mg weekly. This treatment lasted for 6 weeks, followed by a 2-week break, and then the participants received a seasonal flu vaccine.
Blood samples were collected to measure antibodies against different influenza strains, both in the vaccine and not, before and 4 weeks after the flu vaccination.
The study's preliminary results showed that RAD001 was generally well-tolerated, particularly at the 0.5 mg daily and 5 mg weekly doses.
The study's primary goal was to observe if RAD001 could boost immune response in elderly volunteers. This was determined by measuring the increase in antibody levels (hemagglutination inhibition or HI titers) against the flu virus in response to the seasonal flu vaccine. An increase of at least 1.2 times the base level was deemed significant, as this level of increase has previously been associated with a decrease in flu illnesses.
The low-dose RAD001 groups (0.5 mg daily or 5 mg weekly) met the study's primary endpoint—they showed an increase in HI titers. In contrast, the high-dose group (20 mg weekly) did not. Surprisingly, the lower doses seemed just as effective as nearly complete inhibition linked to the high-dose regimen in improving elderly volunteers' immune response. This underscores an important point with mTOR inhibition through the use of rapamycin, and in this case, RAD001—higher doses do not translate to better health outcomes.
In a more detailed look at the results, it appeared that subjects with low baseline flu titers (≤1:40) saw a greater RAD001-associated increase in titers than the overall population. This suggests that RAD001 may be particularly effective in enhancing the vaccine response of subjects at greater risk of flu illness, given their non-protective levels at the start of the study.
Additionally, the results showed that RAD001 seemed to boost the rate of seroconversion—the shift from a negative pre-vaccination titer to a positive post-vaccination titer—especially among subjects with low baseline flu titers.
The benefits of RAD001 weren't restricted to the influenza strains included in the seasonal flu vaccine. Elderly volunteers who were treated with RAD001 also showed higher HI titers and seroconversion rates against two heterologous strains of flu not included in the vaccine, indicating that RAD001 might also provide broader protection against various flu strains, indicating some underlying global immune enhancement through mTOR inhibition.
The underlying mechanism for RAD001's beneficial effects was that it seemed to decrease the percentage of "exhausted" T cells, marked by the presence of PD-1, suggesting a rejuvenation of the immune system.
PD-1, short for Programmed cell Death protein 1, is a type of protein that plays a vital role in preventing the immune system from attacking cells in the body, acting as an immune checkpoint. These checkpoints are crucial in preventing autoimmune reactions. However, over time, these PD-1-positive cells can accumulate, leading to a decrease in the immune system's effectiveness, particularly its response to antigens, which are substances that induce an immune response.
This is particularly impactful for the elderly, whose immune systems naturally decline over time as part of the progression of immunosenscence. With age, the effectiveness of the immune response to infections and vaccines decreases, making the elderly more susceptible to diseases and less responsive to vaccinations compared to younger individuals.
The study highlights the role of RAD001, an mTOR inhibitor, in reducing the percentage of PD-1-positive T cells. Mannick's study suggests that by reducing the PD-1-positive T cells, RAD001 could potentially reverse or slow down some aspects of immunosenescence.
In 2021, Mannick conducted a follow-up clinical trial on the use of rapalog mTOR inhibitors to enhance immune response to the SARS-CoV-2 virus.
Adults over 65 are more susceptible to respiratory tract infections (RTIs). One reason for this heightened vulnerability in older adults could be a less potent type 1 interferon (IFN) immune response.
Interferons are key frontline warriors in the body's defense against viral invaders, triggering the expression of a vast array of antiviral genes that work to inhibit viral replication.
Interferons are a group of signaling proteins that are produced and released by host cells in response to the presence of several viruses. Specifically, type 1 interferons (which include IFN-alpha and IFN-beta) play a critical role in the body's antiviral defenses.
When a cell gets infected by a virus, it releases interferons, which are then picked up by neighboring cells. These neighboring cells, upon receiving the interferon signals, trigger the expression of a wide range of antiviral genes. The proteins produced by these genes help inhibit viral replication, essentially limiting the spread of the virus within the body.
As we grow older, our ability to produce and respond to type 1 interferon can decline. This decreased IFN response means that the body is less able to activate the necessary antiviral defenses, leaving it more vulnerable to viral infections. This can be a critical factor in diseases such as influenza and COVID-19, which are known to severely affect older adults.
Their role is so crucial that deficiencies in the type 1 IFN pathway or the presence of neutralizing autoantibodies against type 1 IFN have been observed in many patients suffering from severe COVID-19 pneumonia, emphasizing their importance in the fight against viral infections, including the SARS-CoV-2 virus.
Mannick focused on the utilization of mTOR inhibitors like rapamycin because inhibiting mTOR has shown efficacy in shielding mice from respiratory infections and enhance their IFN-induced antiviral immune responses.
The primary endpoint objective of the trial was to see if the use mTOR inhibitors would lower the incidence of laboratory-confirmed respiratory tract infections. RTB101, an mTOR inhibitor and an analog of rapamycin, administered at a dose of 10 mg once daily for 16 weeks, was found to be well-tolerated in adults aged 65 and above. Moreover, it successfully increased the expression of IFN-stimulated antiviral genes and decreased the incidence of laboratory-confirmed RTIs. Notably, there was a significant reduction in severe symptoms of laboratory-confirmed RTIs.
The trials affirmed that it is possible to therapeutically target aging biology safely in older adults using treatments like mTOR inhibitors. The trials also suggest that therapies targeting aging biology could help ameliorate certain aging organ system dysfunctions, such as deficient IFN-induced antiviral responses.
mTOR activity is often found to be increased in many cancers, so drugs that inhibit (or slow down) mTOR can potentially be used to treat these cancers.
While mTOR's effects on cancer cells (such as regulating growth and metabolism) have been well-studied, mTOR also has significant, but less reported, effects on the immune system.
Researchers at the Curiel Lab hypothesized that the immune effects of mTOR inhibitors could influence their clinical effectiveness against cancer. Specifically, they focused on how mTOR inhibitors could prevent cancer from forming in the first place via its immune effects, which seems to be a more effective use of these drugs based on previous data.
mTOR helps regulate various immune cells and responses, including Th1 cell function and differentiation, the creation of memory T cells that protect from cancer, and the generation of cells that can either promote or suppress cancer.
Th1 cells are a subset of CD4+ T cells, a type of white blood cell that plays a key role in the body's immune response. Th1 cells, in particular, help coordinate the immune response against intracellular pathogens (like viruses) and also play a role in autoimmunity. mTOR activity has been found to influence the differentiation of CD4+ T cells into Th1 cells, thereby affecting the overall immune response.
After an infection, a small number of the T cells that responded to the pathogen become 'memory T cells'. These cells can live for a long time and provide quick and effective responses if the same pathogen is encountered again. mTOR has a role in the formation and function of these memory T cells, thus contributing to long-term immunity.
The researchers proposed that the ability of rapamycin to prevent or treat cancer might not only be due to its effects on mTOR activity in cancer cells, but also its effects on the immune system.
To test this, they used the same mouse model of skin cancer and found that a molecule called interferon gamma (IFNg) and a type of immune cell (gd T cells) were both important for rapamycin's ability to prevent and treat cancer.
Specifically, IFNg (which was not dependent on rapamycin) helped bring gd T cells to the area of the skin where they could potentially combat cancer, and rapamycin seemed to enhance the anti-cancer activity of these gd T cells.
Rapamycin could also enhance the ability of human gd T cells to kill human squamous cell carcinoma cells, both in a lab dish (in vitro) and in a living organism (in vivo). This suggests that rapamycin might help improve the effectiveness of treatments that involve using gd T cells to fight cancer, which are currently being tested in clinical trials.
By blocking mTOR signaling, mTOR inhibitors like rapamycin could theoretically disrupt the abnormal growth and proliferation of cancer cells, and also modulate the immune system to better fight the cancer.
As the saying goes, "less is more"—and that seems to hold true when it comes to the use of rapamycin and its derivatives. The research of Dr. Joan Mannick sheds light on the subtlety of dosage in determining whether the drug bolsters the immune system or suppresses it.
In Mannick's study, it was not the highest dose but rather the smaller 5mg per week dosing that showed a positive impact on immune function. This outcome underscores the delicate balancing act needed to harness the therapeutic power of rapamycin as an immune booster.
The reason for this intriguing response lies in the structure of mTOR, a central regulator of cell behavior, which operates in two different complexes - mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
The former, mTORC1, is rapamycin's primary target. Acting like a command center, mTORC1 orchestrates cell growth and metabolism, responding to a variety of signals from nutrients and growth factors to cellular energy status. When mTORC1 is activated, it promotes processes such as protein synthesis and ribosome biogenesis, while simultaneously dampening catabolic processes like autophagy.
mTORC2, however, has proven more elusive and isn't as readily affected by acute rapamycin treatment. But it's no less important; it's pivotal for activating and differentiating regulatory T cells. These cellular peacekeepers prevent autoimmune reactions by suppressing overactive immune responses.
When higher doses of rapamycin are used, or the drug is taken daily, it's mTORC2 that ends up being inhibited as rapamycin concentrations increase. The outcome? Immunosuppression. This is why transplant patients, who need to prevent overactive immune responses against their new organs, will take daily doses of rapamycin.
But, if the goal is to reap the immune-boosting benefits of rapamycin without the side effect of immunosuppression, the key lies in lower and cyclical dosing—in humans, this is once every 7 to 14 days. This allows the delicate balance between mTORC1 and mTORC2 to be maintained, enhancing the body's immune responses without tipping the scales towards suppression.
Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179. doi: 10.1126/scitranslmed.3009892. PMID: 25540326.
Mannick JB, Teo G, Bernardo P, Quinn D, Russell K, Klickstein L, Marshall W, Shergill S. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2021 May;2(5):e250-e262. doi: 10.1016/S2666-7568(21)00062-3. Epub 2021 May 6. PMID: 33977284; PMCID: PMC8102040.
Dao V, Liu Y, Pandeswara S, Svatek RS, Gelfond JA, Liu A, Hurez V, Curiel TJ. Immune-Stimulatory Effects of Rapamycin Are Mediated by Stimulation of Antitumor γδ T Cells. Cancer Res. 2016 Oct 15;76(20):5970-5982. doi: 10.1158/0008-5472.CAN-16-0091. Epub 2016 Aug 28. PMID: 27569211; PMCID: PMC5065775.
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