HUMAN LONGEVITY

The Role of Sirtuins in Aging and Neurodegenerative Diseases

Analyzing SIRT1 Mechanisms Using PyMol

In-Woo Park
ILLUMINATION
Published in
9 min readJan 24, 2023

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Photo by Anna Shvets from Pexels

In the early years of life, our brain undergoes rapid development, forming more than a million new neural connections per second. By the age of 6, it reaches approximately 90% of its adult volume, with the final stages of development occurring during our 20’s. This then leaves room for ‘normal brain aging’ to occur, causing occasional memory slips that increase in occurrence over time.

If you’ve read my article, “Reversing Aging With Epigenetic Reprogramming,” you’ll learn that aging is actually due to the loss of epigenetic information. Cells lose their identity and forget what they’re supposed to do, causing stochastic damage in our bodies. In the brain specifically, aging typically causes blood flow to decrease and communication between neurons to become weaker, creating common memory changes that we often notice as we become older. Some of them include:

  • Decreased attention span
  • Difficulty learning something new
  • Inability to multitask
  • Asking repetitive questions
  • Trouble remembering names and events

For the longest time, these symptoms were inevitable. But times have changed. Today the average human life expectancy is close to 73 years, more than double of what it was in 1900. The ability to do this makes us wonder, “what really is aging?”

As we’ve seen in the past, advancements in medicine such as gene therapy or even the development of antibiotics, have been shown to increase the average human lifespan tremendously.

But if we want to further solve the longevity puzzle, we must refrain from looking at aging as a natural process. If anything, aging is a disease in itself and is the underlying cause of many degenerative diseases such as Alzheimer’s or cancer.

In recent years, we’ve made incredible breakthroughs such as the developing epigenetic clocks, or even reversing aging with Yamanaka factors. But for the purpose of this article, I’ll highlight a specific area in longevity research that has received a lot of attention: sirtuins.

Sirtuins and Epigenetics: Understanding the Impact on Gene Expression

Sirtuins are a family of enzymes involved in many cellular processes such as transcription regulation, energy metabolism, cellular homeostasis, and DNA damage repair; just to name a few. Humans have seven known sirtuins (SIRT1-SIRT7), each with distinct functions and locations within the cell.

In the field of human longevity, they’re well known for their gene-silencing properties, hence the name “sirtuin” where “sir” stands for Silent Information Regulator. Their primary function, histone deacetylation, is what allows them to carry out this gene-silencing process.

In our cells, nuclear DNA is packed in the form of chromatins, which are winded around spool-like proteins called histones. On histone tails are these chemical compounds called acetyl groups (−COCH 3) which alter the electrostatic interaction between the positively charged protein and the negatively charged phosphate backbone of DNA. This leads to a more “relaxed” or “unspooled” structure of the chromatin; thus, allowing genes to be transcribed/ accessible.

Euchromatin formed by histone acetylation (Image by Author)

Sirtuins on the other hand regulate the removal of these acetyl groups from histones (histone deacetylation), clearing the path for the positively charged protein to tightly bond with the negatively charged phosphate backbone of DNA. This tightened form of chromatin, also known as heterochromatin, prevents genes from being transcribed as a result of its tight structure.

Heterochromatin formed by histone deacetylation (Image by Author)

These patterns of gene activation and inactivation form our epigenome, which is responsible for how our DNA is being expressed. While patterns of the epigenome do not alter the DNA sequence itself, they control how the sequence is being read and interpreted, leading to different characteristics and functions of each cell in our body, despite all cells containing the same set of DNA.

As David A. Sinclair likes to explain it, you can think of our DNA, or our genome, as a grand piano, with each gene representing a key that plays a certain note. However, it’s up to the epigenome, or the pianist, that decides how and what to play. Thus, as you might expect, maintaining this epigenome is crucial, and sirtuin activation plays an important part in regulating it.

But what exactly is in charge of preserving the sirtuins themselves?

The Importance of NAD+

Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme found in every cell in our bodies, involved in dozens of processes ranging from cellular metabolism to even stress response. The molecule exists in two forms: NAD+ and NADH, both highly critical for our bodies. But in relation to sirtuins, we’ll focus on NAD+.

Besides its central role in energy production, NAD+ plays a huge role in sirtuin activation. When NAD+ levels are high, sirtuins are activated, allowing them to carry out their enzymatic activity. When NAD+ levels are low, the opposite occurs: fewer sirtuins are active.

Here’s a visual simulation on PyMol that I performed of NAD+ binding with SIRT1.

(Left) Open State Human SIRT1, PDB code: 4KXQ (Image by Author) | (Right) Closed State Human SIRT1, PDB code: 4IG9 (Image by Author)

The image on the left shows SIRT1 in its open state, where it is not bound to NAD+. This protein structure demonstrates an inactive form of the sirtuin. On the other hand, the image on the right shows SIRT1 in its closed state, where it is bound to NAD+ (pink molecule). This structure demonstrates an active form of the sirtuin.

As we age, the levels of NAD+ in our bodies decrease, which can be caused by a number of factors, such as increased usage by enzymes like CD38 or decreased production in the body. This decrease in NAD+ levels leads to a reduction in sirtuin activity, which can affect the regulation of gene expression and result in various issues in the body.

Sirtuins Repair DNA Damage, with a Catch

Another big function of sirtuins that make them so vital is the ability to repair DNA damage. Despite the trillions of DNA double-strand breaks (DSB) that occur in our bodies every day, our cells are still well equipped to handle them, with sirtuins (specifically SIRT1, SIRT6, and SIRT7) being a key part of the repair process.

Typically, sirtuins activate DNA repair proteins when there are small amounts of DNA damage. For example, SIRT1 deacetylates and activates the DNA repair protein PARP1 (poly ADP-ribose polymerase 1). Here’s a simulation of what that looks like:

Structure of Human PARP-1 bound to a DNA double-strand break, PDB code: 4DQY (Image by Author)

However, when damage levels increase, SIRT1 leaves its original post and relocates to the site of damage. The same is observed for SIRT6 in humans and mice. In the occurrence of DNA double-strand breaks, SIRT6 leaves its original post and binds to the specific site of damage, and facilitates repair through the non-homologous end joining (NHEJ) pathway.

The predicted binding affinity by molecular docking analysis shows binding between SIRT6 and DSB to be significant | Source: elifesciences.org, edited with permission

We can compare this process with what often happens during wars. For example, the Vietnam war is one particular instance when many men departed for battle and no farmers remained to care for the farms back home. In many rural villages, this led to food shortages and economic difficulties.

The same occurs in our cells when sirtuins leave to repair DNA damage. Gene expression that they’re normally responsible for has been disrupted by the time they’ve come back. We call this epigenetic noise.

Model for Large-Scale Chromatin State Transitions | Source: Cell.com

When noise accumulates within a cell, epigenetic information is lost, causing cells to lose their identity as well as their original function. When one or two of our cells are affected, we’ll hardly notice. But as more and more cells lose their epigenetic information, we’ll notice decreases in tissue function and regenerative capacity; in other words, aging.

Our bodies start to deteriorate and our ability to self-repair is weakened, opening the door for a wide range of diseases to enter. This includes cardiovascular disease, osteoporosis, and cancer; to name a few. It also contributes to the progression of neurodegenerative diseases, including the disease that so many of us dread: Alzheimer’s.

SIRT1 and Neurodegenerative Diseases

Like cancer, neurodegenerative diseases are common products of aging and are often accelerated as we become older. In the central nervous system (CNS), SIRT1 is involved in the regulation of neural plasticity, which is the brain’s ability to create new neural pathways and adapt to new information. This process is important for learning and memory and is thought to be impaired with less sirtuin activity.

SIRT1 also acts as a neuroprotective agent in the brain. It can modulate the expression of genes involved in oxidative stress, inflammation, and cell death, which are all processes that contribute directly to the development of diseases in the brain. Additionally, SIRT1 has been shown to promote the survival and differentiation of neurons, which is crucial for maintaining the structural and functional integrity of the nervous system.

In Alzheimer’s disease, SIRT1 regulates the clearance of amyloid-beta, a protein that forms plaques in the brain and is highly associated with the disease. This is achieved through multiple mechanisms:

  • Lysosome Activation — Lysosomes are organelles that break down cellular waste products including amyloid-beta. SIRT1 has been shown to regulate the expression of the genes involved in lysosome function, which in turn enhances the degradation of amyloid-beta.
  • Autophagy — The cell’s natural way of removing dysfunctional proteins and organelles. SIRT1 induces autophagy by deacetylating proteins such as FOXOs, which then activate genes that are directly involved in the autophagy process, such as LC3.
  • Microglia Activation — Microglia are immune cells of the brain that are responsible for the maintenance of Central Nervous System (CNS) tissue and other forms of damage in the brain. They are also involved in the clearance of amyloid-beta. SIRT1 activates the transcription factor NF-κβ which leads to the expression of genes required for microglia activation.
  • Apolipoprotein E Regulation— Apolipoprotein E (Apo-E) is a protein involved in the metabolism of lipids that are linked to the clearance of both amyloid-beta and tau, proteins that highly contribute to the development of Alzheimer's disease.

Similarly, SIRT1 activation also helps prevent the development of Parkinson’s disease, which is another neurodegenerative disorder that can be developed through the accumulation of misfolded alpha-synuclein (α-Syn) protein aggregates, also known as Lewy bodies (LB). SIRT1 acts as a neuroprotectant by downregulating the expression of certain proteins thus, reducing alpha-synuclein aggregates.

Furthermore, SIRT1 plays a significant role in not just Alzheimer’s and Parkinson’s disease, but also in other neurodegenerative disorders, which goes to show how crucial sirtuin activity actually is for our health and wellbeing. As we continue to make advancements in the field of human longevity, the study of sirtuins will help us further understand the underlying causes of aging and degenerative diseases.

Maintaining Sirtuin Activity Today and Tomorrow

There are a number of ways to maintain sirtuin activity even now. Simple strategies such as caloric restriction, regular exercise, and intermittent fasting have all been shown to enhance sirtuin activity. There are also supplements such as Urolithin A or NMN that are the closest we’ve ever gotten to the pill of immortality.

However, these interventions can only take us so far. Genetic disruptions or DNA damage will happen regardless of how many supplements or dietary restrictions we hold ourselves to. To fully achieve rejuvenation, strategies such as gene editing or cellular reprogramming has to further develop. But considering the incredible breakthroughs that are announced every day, our ability to overcome aging is within grasp.

To Summarize

  • Sirtuins can perform histone deacetylation to regulate gene expression
  • Loss of NAD+ results in decreased sirtuin activation
  • Sirtuins can repair DNA damage but leave their original site in the process, leading to disruptions in gene expression at the original site
  • The accumulation of epigenetic noise (loss of epigenetic information) is the underlying cause of aging
  • Through multiple mechanisms, SIRT1 acts as a neuroprotective agent, leading to the prevention of many neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease

PyMol resources

Open-state Human SIRT1:

fetch 4KXQ

Closed-state Human SIRT1:

fetch 4IG9

Human PARP-1 bound to a DNA double strand break

fetch 4DQY

Colour-blind friendly imaging on PyMol:

bg_color white

set antialias=1

set orthoscopic=1

set gamma=1.15

set cartoon_fancy_helices, 1

set cartoon_fancy_sheets, 1

set_color wred, [0.788,0.000,0.140]

set_color wblue, [0.31,0.506,0.686]

set_color wgold, [0.855,0.647,0.125]

set_color wgreen, [0.134,0.545,0.134]

set_color wgray, [0.800,0.800,0.800]

set_color wrose, [0.65,0.47,0.55]

set_color wpurple, [0.37,0.31,0.62]

set_color mpurple, [0.75,0.57,0.80]

set_color mpgrey, [0.73,0.68,0.82]

set ray_shadows, 0

set ray_trace_fog, 1

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In-Woo Park
ILLUMINATION

17yo | Bio-Researcher | TKS Innovator | Pharmacy Assistant | Human Longevity