Scientists have succeeded in reversing mouse aging by rejuvenating old cells found in muscles, tissues and organs – one step closer to their ultimate goal of reversing human aging.
Researchers in Juan Carlos Izpisua Belmonte’s lab employed four genes to switch mature cells back to embryonic-like ones, prolonging life in mice suffering from an accelerated-aging disorder and improving their ability to recover after injury. This approach extended their lives significantly.
1. NAD+
NAD+ plays an essential role in every cell in our bodies, fueling many metabolic processes that keep us alive. Additionally, DNA repair may occur with its help as well as aiding immune response against chronic illnesses such as cancer or inflammation.
As people age, their NAD+ levels naturally decline and this can interfere with cell function; however, scientists have discovered that by raising NAD+ levels in cells they can reverse some of the negative effects associated with aging.
Scientists recently found that NMN can increase cell performance by stimulating SIRT1 to eat more, producing more NAD+. As SIRT1 helps slow the progression of aging, this medication may serve as an anti-ageing treatment.
Researchers are now using NMN to boost NAD+ levels in various organs and tissues of mice, observing that it improves their health and longevity. Researchers believe it can reverse signs of aging such as slow metabolism, poor muscle regeneration and reduced memory function through increasing NAD+ levels.
They have also discovered that NMN can reverse dysfunction of the circadian clock in older mice, an important finding given that this clock is directly tied to cellular senescence and ageing processes. Thus, strategies which restore NAD+ in senescent cells could potentially be used to reprogram them and improve their ability to regenerate muscles and other organs.
Skeletal muscle, liver and an unnamed type of adipose tissue all experience decreased levels of NAD+ as people get older, due to increased enzyme activity that consumes NAD+ from these tissues and further depletes it.
This study involved giving mice NMN and rapidly seeing their NAD+ levels rise; thus reversing signs of aging within just one week in muscles, tissues and livers. Their authors were encouraged by their results and are planning long-term oral administration of NAD+ precursors such as NR and other precursors in humans via randomized control trials (RCT), the gold standard of scientific research.
2. Yamanaka factors
Shinya Yamanaka astounded biologists when he demonstrated, in 2006, how a set of transcription factors–agents that activate genes–could return differentiated cells to an embryonic state using transcription factor activation alone. This process erased any markers on their epigenome that gave each cell its identity and contributed to ageing processes within each organism; for his work Yamanaka received half the 2012 Nobel Prize in Medicine1.
Researchers examined whether transcription factors could turn back time on cells in vivo–that is, inside an animal rather than in a laboratory dish. After discovering that selectively reprogramming some cells led to more youthful phenotypes in mice, researchers began searching for ways to target expression of these factors selectively in certain organs and tissues.
Scientists have used Yamanaka factors to manipulate fibroblasts – connective tissue cells–back into embryonic form, creating so-called induced pluripotent stem cells (iPSCs). iPSCs can then transform into any cell type in the body.
But iPSCs can also be used to rejuvenate existing cells by clearing away epigenetic marks that cause them to age. A team led by Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies in San Diego, California successfully reversed aging in mice by expressing Yamanaka factors only in certain neurons–namely those belonging to part of their cerebral cortex called a-CaMKII neurons.
Researchers found that when mice’ neurons were exposed to repeated exposure of Yamanaka transcription factors (OSKM, or Oct4, Sox2, Klf4, and c-Myc), lifespan increased on average by 18 weeks on average. They also noticed a partial reversal in patterns of DNA methylation–an indicator associated with aging and cancer–in these neurons.
Although these changes may have reduced cellular senescence, the team still noticed many signs of aging in mice, such as an increase in perineuronal net units in their brain. However, continuous induction of YF expression would likely result in unchecked cell growth and tumorigenesis.
Scientists decided to only reprogram neurons in the cerebral cortex of mice by administering doxycycline to them; this allowed them to express OSKM genes for two days before stopping expression altogether.
3. Telomerase
Telomeres are essential components of chromosomes that act as protective “caps” on DNA molecules. Over time, however, their length gradually diminishes until they eventually force a cell into self-destructing (apoptosis) or becoming damaged and losing function altogether.
Cells use an enzyme known as telomerase to combat the shortening of telomeres, however as we age the gene responsible for producing this enzyme becomes inactive and our telomeres become shorter as a result of our DNA becoming damaged and we begin experiencing the signs of aging.
Researchers have attempted to stimulate telomerase by inserting an artificial sequence of repeated nucleotides into cells, though this process can be costly and only works in certain types. Scientists also worry that stimulating telomerase in all cells might promote cancerous growth or cause other harmful long-term consequences.
Scientists recently made an important breakthrough by discovering that PGC1-alpha, which promotes mitochondrial activity, can also activate telomerase. By injecting alpha lipoic acid (ALA), they were able to increase PGC1-alpha and thus activate telomerase in several cell types; their injection also resulted in longer telomeres on mice as well as signs of rejuvenation.
Scientists were particularly amazed at the results in brain cells, which are particularly essential to brain health. After increasing telomerase in these cells, they observed that nerve cell coverings regrew, as did new brain cells produced from stem cells; additionally, mice displayed improved behaviors and reversed degeneration of both spleens and testes.
Reversing aging through increasing telomerase activity is not only exciting scientifically but may have profound ramifications for human health as well. Studies on healthy humans have shown that certain activities, like exercise, are associated with higher levels of telomerase. Also intriguingly, reductions in psychologic distress such as intrusive thoughts, anxiety and depression have been found to correspond with higher telomerase activity levels. Further investigation will need to take place before conclusively deciding whether this process can extend human lifespan; but this early research gives hope!
4. ICE
Sinclair’s team used a novel approach in their laboratory to combat aging: they created an inducible changes to epigenome (ICE) chemical cocktail. Instead of altering DNA coding sections that may trigger mutations, ICE modifies how DNA folds causing temporary cuts which quickly heal from sunlight, chemicals or other sources of damage similar to what occurs with age–thus helping turn back time on cells throughout the entire body.
Studies with mouse embryonic fibroblasts (MEFs) conducted by researchers showed that ICE treatment can significantly decrease their estimated DNA-damage age and boost expression of genes related to cell senescence. They also demonstrated how it could attenuate progeroid effects without altering cellular identity or identity.
Sinclair’s team first conducted experiments using ICE on cells lining the retinal ganglion in the back of the eye, the main sensory nerve for vision. Reversing time on these cells enabled the team to cure blind mice from their condition. Next they tested three out of the four Yamanaka factors to revive brain, muscle, and kidney tissue at once for rejuvenation – effectively returning these tissues back to much younger levels than before.
Recent research by ICE suggests it may also combat aging by counteracting the effect of telomerase on chromatin, the molecular structure that regulates gene expression. When activated, telomerase stops shortening of chromosome ends and prevents cells from programmed cell death; when switched off however, damage increases and genomic instability increases further.
Sinclair and her team are still exploring methods to deliver a cocktail evenly to every cell in mice, but other groups have made progress in this area. A team from a biotech firm recently used gene therapy to reverse aging in mice by stimulating SIRT6 production; an approach which may eventually allow scientists to slow or even reverse human aging.
