Next Generation Anti-Aging Therapeutics

By webnad

As the future unfolds, new and improved therapies aimed to mitigate age-related physiological decline are being developed. Some of these nascent, anti-aging therapies of the future have received attention for conferring beneficial effects on animal models. However, these potential therapies will become relics of the past if they don’t prove effective in humans.

  1. Gene Manipulation
    1. What Are Genes, and How Can They Be Manipulated?
    2. How Manipulating Genes Affect Aging?
    3. Genetic Manipulation of Rodent Models to Increase Lifespan
      1. Adding Genes that Increase Lifespan
        1. VEGF
        2. TERT
        3. SIRT6
        4. FST
      2. Removing Genes that Shorten Lifespan
        1. xCT
        2. KAT7
    4. Genes Linked to Increased Lifespan in Humans
      1. APOE
      2. FOXO3A
      3. SIRT6
      4. BPIFB
    5. Gene Therapy for Aging
  2. Bioengineered Organs
  3. Cellular Reprogramming
  4. Stem Cell Therapy
  5. Gut Bacteria Transplants
  6. Young Blood Transfusion

Gene Manipulation 

While our lifestyle choices are the main determinant of how long we live, our genetics are estimated to account for 25% of the variation in human longevity. Therefore, it may be possible to manipulate specific age-related genes to help us live longer while in good health.  

How Can Genes Be Manipulated?

Studies have shown that human lifespan is heritable, with genes determining an estimated 12% to 25% of lifespan duration. To make a protein, our cells first transcribe a gene from our DNA into messenger RNA (mRNA). The transcribed gene, mRNA, is then translated into a functional protein.  

We can manipulate a gene at either the DNA or mRNA level. To add a gene to a cell, the gene can be inserted directly into DNA, or it can be transferred into a cell in the form of mRNA. Either way (leaving the technical obstacles aside), the cell should be able to make a functional protein from that gene. Similarly, to remove a gene from a cell, the gene can be deleted from DNA, or the mRNA for that gene to be degraded.  

How Can Manipulating Genes Affect Aging?

With aging comes changes in gene activation. That is, compared to cells from younger organisms, the cells of older organisms have sets of genes that are turned on and sets of genes that are turned off. By manipulating these genes, we can add back the genes that have been turned off and subtract the genes that have been turned on in the hopes of modulating the aging process. This is one way to look at how gene manipulation can affect aging. 

Also, by manipulating specific genes, we are essentially manipulating specific proteins. It is these proteins that do most of the work necessary for our cells to function. Dysfunctional proteins can lead to dysfunctional cells, which can lead to dysfunctional organs, leading to age-related diseases that lead to death/shortened lifespan. By restoring dysfunctional proteins, we may be able to prevent age-related disease and increase lifespan at the subcellular level.

Genetic Manipulations of Rodent Models that Increase Lifespan 

Multiple model organisms have been used to study the genes associated with aging and increasing lifespan, but the focus here will be on rodent models, which are genetically closer to humans than other commonly used models such as fruit flies, yeast, and nematodes. As of 2018, 50 genes have been identified to be associated with increasing the lifespan of rodents (summarized here). Therefore, only genes recently discovered to increase rodent lifespan will be discussed here. 

Adding Genes that Increase Lifespan 

VEGF: VEGF is a protein associated with mitigating the age-related loss of small blood vessels (capillaries). Delivering the VEGF gene to aged mice increases male lifespan by nearly 50% and female lifespan by nearly 40%. VEGF also reduces fat accumulation, liver inflammation, muscle weakness and loss (sarcopenia), bone loss, and tumor burden. 

TERT: TERT is the gene that codes for the telomerase enzyme, which extends the telomeres of our DNA. Delivery of the TERT gene to age-accelerated mice extends their lifespan by 20%. Furthermore, delivery of TERT via intranasal injection extends mouse lifespan by about 40%. 

SIRT6: The SIRT6 gene codes for the sirtuin 6 enzyme, which modulates sugar and fat metabolism and is associated with increased lifespan. When this gene is overactivated in mice it increases the lifespan of males by 11% and females by 15% while also improving glucose homeostasis.

FST: The FST gene codes for the follistatin protein, a signaling protein involved in muscle growth. When delivered via intranasal injection, FST extends the lifespan of mice by about 30% and improves their physical performance and coordination. 

Removing Genes that Shorten Lifespan 

xCT: The xCT protein is an amino acid (building blocks of proteins) transporter. It moves glutamate out of cells and cysteine into cells. Genetically manipulated “knock-out” mice with the gene for xCT deleted live 13% longer than normal mice, and have improved memory with reduced brain inflammation.  

KAT7: KAT7 is an enzyme involved in epigenetic modulation (histone acetyltransferase).  Removing the gene for KAT7 using a technology called CRISPR-Cas9 slightly (<10%) prolongs the lifespan of naturally and prematurely aged mice while also alleviating liver senescence (aging). 

Genes Directly Linked to Increased Lifespan in Humans 

We will not likely see human studies testing the effects of gene manipulation on lifespan any time soon. This is due to the costs and time it would take to undertake such studies. However, we can infer which genes may provide effects conducive to increased lifespan by looking at the genetics of individuals who have already lived longer than average lifespans. Unlike the previously mentioned rodent studies, it is the variation in specific genes that are different between humans, rather than the absence or addition of genes, that seem to contribute to increased lifespan. 

APOE: APOE is a protein that carries cholesterol through the bloodstream and is involved in the transport of cholesterol and fat into brain cells. The APOEε3 variant is the most common, while the APOEε2 variant has been observed in very old individuals. In contrast, the APOEε4 variant is associated with an increased risk of age-related diseases like Alzheimer’s disease and cardiovascular disease, which can shorten lifespan. 

FOXO3A: A particular variant of FOXO3A (rs2802292) has been associated with increased longevity, especially in males. It also has protective effects against age-related diseases like cardiovascular disease and cancer. This gene variant codes for a protein (transcription factor) that modulates genes related to insulin and oxidative stress — damage caused to cells by excessive levels of reactive oxygen species. 

SIRT6: A variant of the SIRT6 gene has been observed in Ashkenazi Jewish centenarians. Compared to the normal variant, this variant (centSIRT6) displays increased DNA repair and more robust cancer cell-killing capabilities. 

BPIFB4: A variant of a gene called BPIFB4 called the longevity-associated variant (LAV)-BPIFB4 has been observed in long-lived individuals (older than 95 years old). LAV-BPIFB4 has also been shown to eliminate senescent cells and raise NAD+ levels in mice. BPIFB4 is normally involved in fighting infections. 

Gene Therapy for Aging 

Gene therapy, usually defined as adding a gene to an individual’s cells, has already been proven as a successful treatment for many diseases. Currently, most gene therapies target cancer, while others are used to treat genetic diseases and infections. There are no gene therapies approved for the treatment of aging, as aging is not considered a disease. However, in the future, it is possible that so-called longevity genes could be used to treat age-related diseases. For example, the longevity variant of FOXO3A may be utilized to treat cardiovascular disease, or the longevity variant of SIRT6 may be used for the treatment of cancer. 

Bioengineered Organs 

Succumbing to a fatal age-related condition like cardiovascular disease or neurodegenerative disease can potentially shorten the duration of our lifespan. Since many age-related diseases with high mortality risks are associated with the dysfunction of a particular organ, replacing a diseased organ could prove to prolong lifespan. While organ transplants have saved many lives, problems arise from limited availability and immune system rejection, especially from older donors. Thus bioengineered organs — organs made in a lab — could provide a readily available alternative to organ donation. While we are far from bioengineering parts of the human brain, we are closer to generating bioengineered hearts and blood vessels, which could potentially prevent death caused by cardiovascular disease and heart failure. 

Cellular Reprogramming 

While still in its infancy, if honed properly, cellular reprogramming technology could be the future of anti-aging therapy. Celluar reprogramming has been shown to reverse the aging of mice and rejuvenate human skin cells by making them 30 years younger. This process is achieved through nobel-prize winning technology, involving what are called Yamanaka factors, which trick older cells into reverting back to an earlier developmental stage, essentially reversing cellular aging. Thus, in the future we may be able to almost literally reverse aging, at least in some organs.  

Stem Cell Therapy

Adult stem cells are the cells responsible for regenerating tissue, like our muscle and immune cells. As we age, stem cells become exhausted and are no longer able to regenerate tissue efficiently. Thus, stem cell therapy could be another way to slow aging by rejuvenating tissue regenerative capacity. Stem cell therapy may give a way to overcome diseases like sarcopenia — age-related muscle weakness and deterioration, which is influenced by defective muscle stem cells. Further into the future, stem cells may even be utilized to replace adult cells. For example, Parkinson’s disease involves the degeneration of a relatively small set of neurons in the brain. Someday, it may be possible to replace these neurons using stem cell therapy. 

Gut Bacteria Transplants 

Fecal matter banking at a young age for future transplantation during older years is a way that scientists have proposed to rejuvenate gut health as we get older. Currently fecal banking is performed to transplant fecal matter from healthy donors to aged individuals with bowel diseases like bacterial infection. Even though transplanting fecal matter from healthy to aged individuals has shown effectiveness in alleviating bacterial infection, scientists have recently proposed banking fecal matter when we are young. By transplanting our younger fecal matter to our guts when we age, we may overcome differences in gut microbes that make immune reactions more likely.

Young Blood Transfusion

The idea that young blood can rejuvenate the old has led to experiments involving heterochronic plasma exchange – injecting aged animals with blood from younger ones. Experiments using mice have utilized this method and shown that infusing blood from young mice into older mice rejuvenates multiple tissues, including the brain, muscle, liver, and bone. Utilizing heterochronic plasma exchange may provide a way to reverse aging, especially as studies come out showing whether this technique is effective in aged individuals.

(Ma et al., 2022 | Cell Stem Cell) Heterochronic plasma exchange, infusing blood from young rodents into older ones, rejuvenates multiple tissues from the brain, to muscle, to liver, and bone.

Another anti-aging development related to blood exchange entails exchanging old blood plasma with saline and albumin – globular proteins found in blood. This “neutral blood exchange” enhances the production of new neurons in the brain, along with the development of new muscle in mice.

An interesting therapeutic development that has taken hold is using umbilical cord blood. The idea behind this strategy is to rejuvenate tissue by infusing blood plasma from an early developmental stage into aged adults. The levels of a metabolite called arachidonic acid declines as people age, but research has shown that rejuvenating the blood supply with umbilical cord blood in rodents increases arachidonic acid levels. Arachidonic acid is just one biological marker of aging, but other studies have shown that injecting umbilical cord blood into aged mice improves their memory and learning capabilities.

From using the blood of young animals to fight aging to banking fecal matter from our younger years, the future is full of new potential treatments for age-related physiological decline. The prevailing questions that will decide whether we invest in these therapies will relate to how cost effective they are.

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