NAD+ and the Hallmarks of Aging Series – Part 7: Cellular senescence – ALIVE BY SCIENCE – Bioavailable NAD+ Boosters

NAD+ and the Hallmarks of Aging Series – Part 7: Cellular senescence

Cellular senescence – Aging at the cellular level

Cellular senescence is generally defined as a loss of the ability to divide followed by some secretive phenotypes. This phenomenon is first described by Hayflick in 1961, which is primarily caused by telomere shortening or other kinds of DNA damage. As DNA damage is typically inevitable during the DNA replication processes, senescent cells are actually universal: they do not only exist in the old tissues, but also in young tissues.

A previous study suggests that 8% of cells are senescent cells in the liver of young mice and in very old mice, the percentage of senescent cells reaches 17% (read more at Wang et al. 2009 https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2009.00481.x). Similar results were observed in the skin, lung, and spleen, but no changes were observed in the heart, skeletal muscle, or kidney, suggesting these issues are more resistant to the age-related accumulation of senescent cells.

 

Cellular Senescence
Senescent cells (colored) in young and old tissue (Wang et al. 2009)

 

Cellular senescence as a protective mechanism in young tissue

Since the number of senescent cells increases during aging, it is easy to assume that cellular senescence is a “bad thing” that contributes to aging. However, as a genetically “programmed” pro-cedure, there is an evolutionary purpose. Senescent cells prevent the propagation of damaged cells by actively suspending their ability to replicate and also trigger their removal by recruiting immune cells.

Therefore, in well-maintained tissues (e.g., young tissue with good immune function), senescence is potentially a beneficial mechanism that removes the damaged and oncogenic (cancerous) cells and it will remain to be beneficial as long as this tissue maintains an efficient cell replacement system, including the clearance of senescent cells and generation of progenitors to replace those senescent cells.

But it aggravates the damage in old tissue…

As one could imagine, in aged organisms, the maintenance system mentioned above will become inefficient and may exhaust the regenerative capacity of progenitor cells. This functional decline will eventually result in the accumulation of senescent cells that aggravate the damage and contribute to aging.

Senescent cells show dramatic alterations in their secretome (i.e., the molecule they released to the intercellular environment), which is particularly enriched in proinflammatory cytokines. This behavior is referred to as the “senescence-associated secretory phenotype”, or SASP. Originally, these inflammatory factors will recruit the immune cells. In young tissues, the immune cells are usually responsive and will effectively remove the senescent cells. However, in old tissue, the immune system usually fails to respond to the signal and remove senescent cells. This results in the accumulation of senescent cells in the tissue, as well as chronic inflammation in old tissue (aka, inflamaging).

 

Cellular Senescence diagram
The two faces of cellular senescence (Lopez-Otin et al., 2013)

 

NAD+ supplementation previents senescence

As previously mentioned, cellular senescence is mostly driven by DNA damage. The ATM kinase, encoded by the ataxia telangiectasia-mutated (ATM) gene is a master regulator of the DNA double-strand break repair responses and contributes to cellular redox balance. In response to DNA damage, ATM is activated and then phosphorylates several downstream proteins that enhance DNA repair. In ATM-deficient cells, mitochondrial dysfunction and cellular senescence are observed.

Senescence is mediated by stimulator of interferon genes (STING). In March 2021, Yang et al. show that the show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence (https://onlinelibrary.wiley.com/doi/10.1111/acel.13329#).

 

Cellular Senescence3
NR supplementation reduced the number of senescent cells (blue, Yang et al., 2021)

 

NAD+ supplementation also prevents inflammatory phenotypes of senescent cells

Moreover, NR treatment also reduced inflammatory molecules secreted by senescent cells by promoting mitophagy (the autophagy of mitochondria). In addition, NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves physical function in Atm mutated mice.

 

Cellular Senescence4
NR supplementation reduced inflammatory molecules secreted by the senescent cells (Yang et al., 2021)

 

Senolytic compounds

Senolytic drugs are small molecule compounds that selectively kill senescent cells. In animal studies, targeting senescent cells using senolytic drugs alleviates multiple age-related phenotypes and chronic diseases.

One of the most potent senolytic drugs is fisetin. Previous studies show that both acute or intermittent treatment of old mice with fisetin reduced senescence markers in multiple tissues. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan (Yousefzadeh et al., 2018, https://www.sciencedirect.com/science/article/pii/S2352396418303736?via%3Dihub).