Sirtuins and aging

Sirtuins are proteins, and within the context of cellular biochemistry, they function as enzymes. Specifically, they are a family of NAD+-dependent deacetylases and ADP-ribosyltransferases. Here’s a more detailed look at your questions:

Sirtuins are a family of proteins that have been associated with regulating cellular health. They are involved in a range of cellular processes, including DNA repair, inflammation suppression, metabolic regulation, and lifespan extension under certain conditions.

Importance for Cellular Health:

Sirtuins play pivotal roles in cellular health:

  • Metabolic Regulation: Sirtuins are involved in regulating cellular metabolism, responding to changes in nutrient availability, and assisting cells in energy production.
  • DNA Repair: They play a crucial role in repairing damaged DNA, ensuring genetic information remains intact.
  • Cell Survival: Under stressful conditions, such as low nutrient availability or DNA damage, sirtuins can promote cell survival mechanisms.
  • Anti-inflammatory: Some sirtuins can suppress the production of inflammatory molecules, potentially mitigating inflammation-induced damage.
  • Aging and Longevity: While the exact connection between sirtuins and longevity is still a topic of research, some studies, particularly in simpler organisms, have linked increased sirtuin activity to extended lifespan.
  • Mitochondrial Health: Given that mitochondria are essential for energy production in cells, sirtuins’ role in maintaining mitochondrial health directly affects a cell’s vitality and function.

Sirtuins 1 to 7

There are seven known sirtuins in mammals, numbered SIRT1 through SIRT7. Here’s a quick overview of each and their primary roles:

  1. SIRT1:
    • Location: Predominantly in the nucleus but also found in the cytoplasm.
    • Roles:
      • Regulates several transcription factors and co-factors.
      • Involved in energy metabolism, cellular response to stress, and circadian rhythms.
      • Can promote DNA repair and cell survival under stress.
      • Has a role in regulating metabolism, inflammation, and possibly lifespan.
  2. SIRT2:
    • Location: Mainly in the cytoplasm.
    • Roles:
      • Regulates the cell cycle and prevents abnormal cell division.
      • Has a role in metabolism, particularly in the liver.
      • Implicated in neuroprotection.
  3. SIRT3:
    • Location: Mitochondria.
    • Roles:
      • Vital for maintaining mitochondrial function and metabolism.
      • Supports antioxidant defenses by regulating the production of reactive oxygen species (ROS).
      • Protects cells from stress-induced apoptosis.
  4. SIRT4:
    • Location: Mitochondria.
    • Roles:
      • Regulates amino acid metabolism and overall mitochondrial health.
      • Inhibits the production of insulin and other metabolic hormones in the pancreas.
  5. SIRT5:
    • Location: Mitochondria.
    • Roles:
      • Regulates the urea cycle and amino acid metabolism.
      • Modifies certain enzymes to optimize their function under stress conditions.
  6. SIRT6:
    • Location: Nucleus.
    • Roles:
      • Involved in DNA repair.
      • Regulates various aspects of genomic stability.
      • Influences fatty acid metabolism.
      • May have a role in preventing age-associated pathologies.
  7. SIRT7:
    • Location: Nucleus.
    • Roles:
      • Regulates ribosome biogenesis and function.
      • Ensures proper synthesis of proteins within cells.
      • Implicated in maintaining the health and integrity of cellular DNA.

Collectively, sirtuins play a pivotal role in cellular health, metabolism, stress resistance, and potentially longevity. However, it’s worth noting that the understanding of sirtuins is still evolving, and ongoing research continues to uncover more about their diverse roles and potential therapeutic implications.

How Are Sirtuins Created?

Sirtuins are created in cells through the process of protein synthesis, like all other proteins. Their genes are transcribed into mRNA, which is then translated by ribosomes into the sirtuin proteins.

Are Sirtuins Enzymes or Proteins or Both?

All enzymes are proteins (with the exception of a small group of catalytic RNA molecules called ribozymes), but not all proteins are enzymes. Sirtuins are proteins that function as enzymes because they catalyze specific biochemical reactions. Specifically, sirtuins remove acetyl groups from other proteins (a process called deacetylation) in the presence of the molecule NAD+.

History of Sirtuin Discovery

The history of sirtuins begins with the discovery of the SIR2 gene in Saccharomyces cerevisiae (baker’s yeast) in the early 1980s. The SIR2 gene was identified for its role in transcriptional silencing (thus the name “silent information regulator 2”).

By the 1990s, it was observed that an extra copy of the SIR2 gene extended the lifespan of yeast by up to 30%. Conversely, deleting the SIR2 gene shortened yeast lifespan.

Several scientists were involved in the initial discovery and characterization of the SIR genes in yeast, but Dr. Leonard Guarente of MIT is often associated with the landmark discovery of the connection between SIR2 and lifespan extension in the 1990s.

After the discovery in yeast, homologs (genes with shared ancestry) of the SIR2 gene were found in various organisms, from bacteria to humans. In mammals, these homologs are referred to as “sirtuins”, and we have seven of them (SIRT1-SIRT7).

Current State of Sirtuin Research

The number of studies on sirtuins has grown exponentially since their connection to aging was identified. To get an accurate yearly count of studies, one would typically use databases like PubMed to search for sirtuin-related publications year by year. As of my last update in September 2021, there have been thousands of studies involving sirtuins, and the number grows every year. They’ve been researched in the context of aging, metabolic diseases, cancer, neurodegenerative diseases, and more. Given the vast interest in their potential health and longevity implications, this research trend is likely to continue.

Sirtuins As Regulators of aging

Sirtuins have emerged as critical regulators of aging in multiple organisms, from simple yeasts to complex mammals. While all sirtuins have roles that indirectly connect to aging and cellular health, certain sirtuins are more directly associated with the aging process based on research. The association is not direct, it is also still being studied but these sirtuins allow us to get an insight into what can tamper with the process of aging on a cellular level.

Here’s a breakdown:

  1. SIRT1:
    • Role in Aging: SIRT1 is the most well-studied sirtuin in relation to aging. It plays roles in DNA repair, telomere maintenance, and counteracting age-related decline in gene expression.
    • Mechanisms: SIRT1 deacetylates several transcription factors and co-factors, thereby influencing genes related to energy metabolism, stress response, and more.
    • Studies: Caloric restriction, which extends the lifespan in multiple organisms, activates SIRT1. Studies in mice have shown that overexpression of SIRT1 can replicate some benefits of caloric restriction, such as improved metabolic health and resistance to age-related diseases.
  2. SIRT3, SIRT4, & SIRT5:
    • Location: These sirtuins primarily function within the mitochondria.
    • Role in Aging: Mitochondrial health declines with age, impacting cellular energy metabolism. These sirtuins maintain mitochondrial function, which is vital for cell vitality and function.
    • Mechanisms: SIRT3, for example, supports antioxidant defenses, helping to regulate reactive oxygen species (ROS) levels. Excessive ROS can damage cellular components and has been linked to aging and age-related diseases.
  3. SIRT6:
    • Role in Aging: SIRT6 has emerged as a key player in DNA repair, metabolism, and lifespan regulation.
    • Mechanisms: SIRT6 regulates several aspects of genomic stability. Overexpression of SIRT6 can extend the lifespan of male mice.

Research into Sirtuins and Understanding of Aging:

Sirtuins have been instrumental in deepening our understanding of aging at both cellular and organismal levels:

  1. Conserved Longevity Pathways: The discovery that sirtuins can regulate lifespan across multiple species, from yeast to mice, suggests the existence of conserved longevity pathways. This has shifted the way scientists think about aging, viewing it less as an inevitable consequence of time and more as a process that can be modulated.
  2. Caloric Restriction Connection: Caloric restriction, without malnutrition, has been known for decades to extend the lifespan of a variety of organisms. The discovery that sirtuin activity, especially SIRT1, is modulated by caloric restriction tied together nutrient sensing, metabolism, and aging regulation.
  3. DNA Damage and Repair: With age, DNA damage accumulates, leading to genomic instability. Sirtuins, particularly SIRT1 and SIRT6, play crucial roles in DNA repair processes. Understanding these roles has given insights into how cells maintain genetic information integrity and how this impacts aging.
  4. Metabolic Regulation: Aging is intricately linked to metabolic changes. Sirtuins, being critical regulators of metabolism, have provided insights into how metabolic health (or its decline) influences the aging process.
  5. Potential Therapeutic Targets: Given the central roles of sirtuins in aging processes, they have become targets for potential interventions to combat age-related diseases. Compounds like resveratrol, which are believed to activate SIRT1, have been extensively studied for their potential anti-aging properties.

In conclusion, sirtuins have provided a molecular link between metabolism, DNA repair, cellular health, and aging. They’ve illuminated pathways and processes that were previously not understood or not known to be associated with aging, making them a focal point in gerontology and age-related disease research.

What Helps With Sirtuins

Several compounds have been identified that can influence sirtuin expression or activity. Many of these compounds are believed to have an impact on longevity, healthspan, or both. Here’s a list of notable ones, along with relevant studies:

  1. Resveratrol:
    • Impact: A polyphenol found in grapes, red wine, and some berries, resveratrol is believed to activate SIRT1. It has been shown to extend lifespan in various organisms, although its effects in mammals are still under investigation(1, 2).
  2. NAD+ and Precursors (like NMN and NR):
    • Impact: Sirtuins require NAD+ to function. Boosting NAD+ levels or providing precursors like nicotinamide mononucleotide (NMN) (3) or nicotinamide riboside (NR) (4) may enhance sirtuin activity.
  3. Spermidine:
    • Impact: A natural polyamine found in various foods, spermidine induces autophagy, a cellular maintenance and recycling process. It has been shown to extend lifespan across multiple organisms(5).
  4. Metformin:
    • Impact: A drug primarily used to treat type 2 diabetes, metformin is believed to influence sirtuin activity and has been proposed as a longevity-promoting compound(6).
  5. Fisetin:
    • Impact: A plant flavonoid that can enhance SIRT1 expression, reduce inflammation, and eliminate senescent cells(7).
  6. Quercetin:
    • Impact: A flavonoid found in many fruits and vegetables, quercetin can activate SIRT1 and has antioxidant and anti-inflammatory properties(8).
  7. Zinc:
    • Impact: The mineral zinc can enhance SIRT1 protein levels and its deacetylase activity, impacting insulin resistance and metabolic health(9).

These are just a few of the many compounds under investigation. It’s worth noting that while these compounds may influence sirtuin activity or other pathways associated with longevity, their effectiveness in promoting human longevity is still under study.

Inflammation

Inflammation is a complex biological response to harmful stimuli, such as pathogens, damaged cells, or irritants. It’s an integral part of the body’s immune response.

How Cellular Inflammation Happens:

  1. Initial Trigger: Something damages the cells, like a bacterial invasion, a physical injury, toxins, or other irritants.
  2. Release of Chemical Signals: Damaged or threatened cells release chemicals, including substances like histamines, prostaglandins, and bradykinin. These chemicals cause blood vessels to leak fluid into the tissues, causing tissue swelling.
  3. Attraction of Immune Cells: These chemicals also attract white blood cells (leukocytes) to the site of the threat. The white blood cells pass through the walls of the blood vessels and move to the site where they are needed.
  4. Elimination of Threat: White blood cells, including macrophages and neutrophils, start to consume any foreign particles, bacteria, or dead or damaged cells in the area.
  5. Release of Cytokines: As white blood cells work, they release substances called cytokines that amplify or dampen the inflammatory response.
  6. Resolution: Ideally, once the initial cause of cell injury is eliminated, signals stimulate termination of the inflammatory response and begin the healing process.

When is Inflammation Good?

  1. Acute Inflammation: This is a short-term response, usually appearing within minutes or hours after injury. It’s the body’s defense mechanism against infections or injuries. Examples include a sprained ankle or the redness and swelling that can accompany a cut.

When is Inflammation Bad?

  1. Chronic Inflammation: When inflammation persists longer than necessary, it can become harmful. Chronic inflammation can last for weeks, months, or even years. It’s linked to various diseases, including heart disease, diabetes, arthritis, and many cancers.
  2. Excessive Response: Sometimes, the immune response can be too robust, damaging healthy tissues and cells.

Cytokine Storm:

A cytokine storm, or hypercytokinemia, refers to an excessive release of cytokines by the immune system. It can be triggered by various factors, including certain diseases and infections. The severe immune reaction can cause symptoms such as high fever, swelling and redness, extreme fatigue, and nausea. In some cases, a cytokine storm can lead to severe complications, including multiple organ failure.

Cytokine storms are believed to be one of the mechanisms behind severe cases of diseases like COVID-19, where the immune system attacks the body’s own cells and tissues rather than just fighting off the virus.

How to Prevent Cytokine Storms:

  1. Early Detection: Monitoring symptoms and seeking early treatment can help manage conditions that may lead to a cytokine storm.
  2. Medications: Certain drugs can suppress the immune response and prevent or treat cytokine storms. For instance, in the context of COVID-19, dexamethasone, a corticosteroid, has shown promise in reducing the severity of cytokine storms.
  3. Maintain General Health: Regular exercise, a balanced diet, managing stress, and avoiding smoking and excessive alcohol consumption can help maintain a balanced immune system.
  4. Vaccination: Some diseases that can lead to cytokine storms can be prevented with vaccines.
  5. Avoid Known Triggers: If you have a known medical condition that can trigger a cytokine storm, work with your doctor to manage the condition and avoid known triggers.

It’s crucial to remember that inflammation, in and of itself, isn’t “bad.” It’s a necessary part of our body’s defense mechanism. However, like many things in biology, balance is key. Chronic inflammation or an overreactive immune response can be harmful and require medical intervention.

Another method of avoiding excessive inflammation is by raising NAD+ levels, which will make sirtuins, which are the instruments for inflammatory response.

Sirtuins are a family of proteins involved in many cellular processes, including the regulation of cellular health, metabolism, and lifespan. They have also been found to play roles in modulating inflammation.

Sirtuins and inflammation

As mentioned above SIRT1 is among the sirtuins, and SIRT1 is the most studied in the context of inflammation. SIRT1 can suppress the activity of the transcription factor NF-κB, which is a major regulator of inflammatory responses. By deacetylating the p65 subunit of NF-κB, SIRT1 can inhibit its ability to promote the transcription of pro-inflammatory genes.

Other Sirtuins: SIRT2 and SIRT6 also have roles in regulating inflammation. SIRT2 can modulate the activation of the NLRP3 inflammasome, an important component in the inflammatory response, especially in certain autoimmune diseases. SIRT6 can repress the transcriptional activity of NF-κB as well.

Given the involvement of sirtuins in regulating inflammatory responses, it’s plausible to hypothesize that modulating sirtuin activity might impact the progression or severity of a cytokine storm. One way to achieve that is by Boosting NAD+ Levels:

As previously mentioned, sirtuins require NAD+ for their enzymatic activity. Supplementation with NAD+ precursors like nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) could support sirtuin functions.

Raising NAD+to make sirtuins less susceptible to triggering excessive inflammation

Raising NAD+ levels has been proposed as a means to support sirtuin activity, which in turn can modulate inflammation in the body. Before diving into the details, let’s briefly discuss the relationship between sirtuins, NAD+, and inflammation:

  1. Sirtuins and NAD+: Sirtuins are a family of enzymes that require NAD+ to function. NAD+ is a coenzyme present in all cells and is essential for energy metabolism, DNA repair, and various signaling processes. Sirtuin enzymes can remove acetyl groups from proteins in the presence of NAD+, a process called deacetylation. This deacetylation can impact the function of various proteins, including those involved in inflammation.
  2. Sirtuins and Inflammation: Sirtuins, especially SIRT1, can regulate the transcription factor NF-κB, which plays a pivotal role in initiating inflammation. By deacetylating NF-κB or its co-factors, sirtuins can suppress its activity, leading to reduced expression of pro-inflammatory genes.

Given these relationships, here’s how raising NAD+ levels could potentially reduce excessive inflammation:

  1. Increased Sirtuin Activity: Higher NAD+ levels can enhance the activity of sirtuins. When NAD+ levels are sufficient, sirtuins like SIRT1 can effectively deacetylate target proteins, including those involved in inflammatory processes.
  2. Suppression of NF-κB: With enhanced activity, sirtuins can more effectively suppress NF-κB, which can lead to a reduction in the production of inflammatory cytokines and other pro-inflammatory molecules.
  3. Improved Mitochondrial Function: SIRT3, another sirtuin, functions in the mitochondria and can promote mitochondrial health and function. Healthy mitochondria produce fewer reactive oxygen species (ROS), which can otherwise trigger inflammatory processes.
  4. Cell Survival and Anti-apoptotic Effects: Some sirtuins, especially SIRT1, promote cell survival pathways and can reduce apoptosis in certain conditions. This can mitigate inflammation caused by cellular debris.

Boosting NAD+ Levels: To raise NAD+ levels, researchers and some health advocates have explored using precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). These precursors are converted to NAD+ in the body. Studies in animals have shown promising results in terms of increased NAD+ levels and improved health outcomes, but more research is needed, especially in humans.

Caution: While the idea of boosting NAD+ to modulate inflammation is promising, it’s essential to understand that inflammation is a complex response with both beneficial and harmful effects. In some cases, inflammation is crucial for combating infections or healing injuries. In other scenarios, chronic inflammation can be damaging. Modulating NAD+ levels or sirtuin activity could have varied effects depending on the context. Always consult with healthcare professionals when considering interventions related to NAD+ or inflammation.

References

  1. Howitz, K.T., et al. (2003) “Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.” Nature.
  2. Baur, J.A., et al. (2006) “Resveratrol improves health and survival of mice on a high-calorie diet.” Nature.
  3. Zhang, H., et al. (2016) “NAD+ repletion improves mitochondrial and stem cell function and enhances lifespan in mice.” Science.
  4. Mills, K.F., et al. (2016) “Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice.” Cell Metabolism.
  5. Eisenberg, T., et al. (2009) “Induction of autophagy by spermidine promotes longevity.” Nature Cell Biology.
  6. Barzilai, N., et al. (2016) “Metformin as a tool to target aging.” Cell Metabolism.
  7. Yousefzadeh, M.J., et al. (2018) “Fisetin is a senotherapeutic that extends health and lifespan.” EBioMedicine.
  8. Rivera, L., et al. (2009) “Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats.” Obesity.
  9. Jarosz, M., et al. (2017) “Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling.” Inflammopharmacology.