Enhancing Longevity Through TFEB Activation and Nutrient Sensing

TFEB and intermittent fasting

Did you know that TFEB can boost your cells’ ability to remove damaged components, functioning much like an efficient recycling system? Scientists are delving deeper into cellular mechanisms that hold the promise of extending lifespan and improving health.


Two such mechanisms are TFEB activation and nutrient sensing, both of which play pivotal roles in maintaining cellular health and combating age-related decline. Let's explore these fascinating areas in detail and uncover how they can contribute to enhancing longevity.

What is TFEB? Your Cellular Clean-Up Crew

Transcription Factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Structurally, TFEB belongs to the microphthalmia/transcription factor E (MiT/TFE) family and functions by binding to CLEAR (Coordinated Lysosomal Expression and Regulation) elements in the promoters of target genes (R).

How is TFEB Activated?

TFEB activation is regulated through its phosphorylation status. Under nutrient-rich conditions, TFEB is phosphorylated by mTORC1, which sequesters it in the cytoplasm. In response to stress or nutrient deprivation, dephosphorylation of TFEB occurs, allowing it to translocate to the nucleus. Once in the nucleus, TFEB initiates the transcription of genes involved in autophagy and lysosomal biogenesis, enhancing cellular clearance mechanisms (R).

Why TFEB Matters More as We Age

As we age, the regulation of TFEB becomes impaired, contributing to a decline in autophagic and lysosomal functions. This dysregulation is implicated in various age-related diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The accumulation of damaged proteins and organelles due to inefficient autophagy exacerbates cellular dysfunction, highlighting the importance of maintaining proper TFEB activity throughout life (R).

The Role of TFEB in Fighting Ageing

Combating the Hallmarks of Ageing

The hallmarks of ageing, including genomic instability, loss of proteostasis, and mitochondrial dysfunction, are significantly influenced by TFEB activity. By promoting autophagy, TFEB helps maintain proteostasis, ensuring the removal of damaged proteins and organelles. This function is crucial for preserving cellular function and delaying the onset of age-related diseases. Research has shown that enhancing TFEB activity can mitigate the effects of these hallmarks, thereby promoting healthier ageing (R).

Keeping Cells Clean: TFEB and Cellular Clearance

Enhancing Autophagy

Autophagy is the process of degrading and recycling cellular components, and it is vital for cellular health. TFEB activation enhances this process, improving cellular clearance and proteostasis. Efficient autophagy prevents the accumulation of cellular debris, a common feature of ageing cells and tissues. Studies have demonstrated that increasing TFEB activity leads to enhanced autophagic flux, which in turn reduces cellular stress and improves overall cellular function (R).

Loss of Proteostasis

Proteostasis refers to the balance and maintenance of the cell’s protein environment. TFEB plays a crucial role in autophagy, a cellular process that degrades and recycles misfolded or damaged proteins. By activating TFEB, cells can more effectively manage and remove these defective proteins, thereby maintaining protein homeostasis and reducing the risk of protein aggregation diseases, which are common in ageing (R).

Boosting Energy: TFEB and Mitochondrial Health

Supporting Mitochondrial Function

Mitochondria are the powerhouses of the cell, responsible for generating ATP through oxidative phosphorylation. Mitochondrial dysfunction is a hallmark of ageing, contributing to reduced energy production and increased oxidative stress. TFEB activation supports mitochondrial health by facilitating the removal of damaged mitochondria through mitophagy. 

This process not only preserves mitochondrial function but also enhances overall energy metabolism. Research indicates that TFEB activation improves mitochondrial biogenesis and function, thereby supporting cellular energy needs during ageing (R).



Understanding the Role of TFEB in Cellular Mechanisms. This image shows how TFEB influences various pathways to combat hallmarks of aging and related diseases. Source: ScienceDirect

Protecting Our DNA: TFEB’s Role in Repair and Epigenetics

Maintaining Genomic Integrity

Ageing is associated with increased DNA damage and epigenetic changes that impair cellular function. TFEB activation influences DNA repair pathways and modulates epigenetic marks, preserving genomic integrity and promoting longevity. By maintaining efficient DNA repair mechanisms, TFEB helps prevent mutations and chromosomal aberrations that contribute to ageing and disease. 

Additionally, TFEB enhances autophagic processes, aiding in the removal of damaged DNA and other nuclear debris. This combined action reduces the accumulation of genetic mutations, maintaining genomic stability and preventing age-related genetic damage (R).

Nutrient Sensing: Balancing Act for Longevity

Interplay with Nutrient-Sensing Pathways

Nutrient sensing is a critical aspect of cellular metabolism and longevity. Pathways such as mTOR (mechanistic target of rapamycin) and AMPK (AMP-activated protein kinase) respond to nutrient availability and regulate cellular growth, metabolism, and autophagy. TFEB interacts with these pathways, modulating their activity to promote cellular health. 

Under nutrient-rich conditions, mTOR inhibits TFEB by phosphorylating it, whereas nutrient deprivation activates TFEB. This dynamic interplay ensures that cells can adapt to varying nutrient conditions, maintaining homeostasis and promoting longevity (R).

Reducing Inflammation: TFEB’s Anti-Inflammatory Benefits

Anti-Inflammatory Effects

Chronic inflammation is a key driver of age-related diseases. TFEB activation has anti-inflammatory effects, reducing the production of pro-inflammatory cytokines and promoting the resolution of inflammation. By keeping inflammation in check, TFEB supports healthier ageing and reduces the risk of chronic diseases. Research has shown that TFEB can inhibit the activation of NF-κB, a key regulator of inflammation, thereby reducing the inflammatory response and its associated damage (R, R).

Stopping Cellular Ageing: TFEB and Senescence

Inhibiting Cellular Senescence

Cellular senescence is a state where cells stop dividing and secrete harmful factors that contribute to tissue damage and inflammation. TFEB activation can help inhibit senescence, promoting cellular renewal and regeneration. This process is essential for maintaining tissue health and function as we age. Studies have demonstrated that activating TFEB can decrease the expression of senescence markers and promote the clearance of senescent cells, thus enhancing tissue repair and regeneration (R, R).

Applying TFEB Research: Practical Approaches

Harnessing TFEB for Therapeutic Purposes

Researchers are exploring ways to harness TFEB activation for therapeutic purposes. Potential strategies include dietary interventions, pharmaceuticals, and lifestyle changes aimed at enhancing TFEB activity and improving autophagy. For instance, caloric restriction and intermittent fasting have been shown to activate TFEB, promoting autophagy and longevity. Additionally, compounds such as trehalose and resveratrol are being investigated for their potential to activate TFEB and enhance cellular clearance mechanisms (R, R).

Conclusion: The Future of Ageing Research

As our understanding of TFEB and nutrient sensing grows, so does our potential to improve health and longevity. By focusing on these cellular mechanisms, we can develop innovative strategies to enhance the ageing process and improve quality of life.

Learn more about how you can use intermittent fasting to activate TFEB here.

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Written By Natasha Jordan

BHSc Nutritional Medicine, International health - University Of Queensland

Diploma In Dermal Science - AACDS

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