The near future of longevity medicine

Highlights:

• Rapidly developing technologies that could be called the near future of longevity medicine are digital health, geroprotectors, stem cell therapies, gene therapies and regenerative medicine
• Most of the interventions are still in clinical trial phase but some of them such as Dermagraft or Carticel in regenerative medicine and CAR T cell therapy are already avaliable
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Introduction

Currently, plenty of intellectual and financial resources are invested in longevity medicine which focuses on combating the aging-related and chronic disorders. Longevity or anti-aging medicine emerged at the beginning of the 90s and has been a hot topic since. However, we still do not have any fundamental longevity tools ready in our hands. Digital health already exists but is full of flaws and troubles. Gene therapies, stem cell research, and geroprotectors are nothing new, but most of them still face many years of research and clinical trials before they will be widely available. What would be the nearest future of longevity medicine? Will we manage to take advantage of it during our lifetime?

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Digital health

Let us start with a technology known to us – digital health, defined as using digital data and communication technologies to collect, share, and analyze health information. Digital health technologies give unique opportunities to optimize both health care delivery and clinical research. Digitalization covers patients’ registration, health record databases, or e-prescriptions. However, this is not all. A fantastic example of digital health usage can be deep learning technology, which was successfully implemented e.g. in cancer research to detect lymph node metastases after the breast cancer diagnosis. Next, mobile applications for disease management have been introduced to make treatment and communication easier. One of the first such applications was BlueStar for diabetes patients. Another form of digital health is the use of wearables. The ongoing Apple Heart Study measures if Apple Watch can identify heart conditions such as atrial fibrillation. Such personalized digital health technologies might improve engagement in self-care and help with physician-patient communication (1). 

Interestingly, numerous research reports state that the COVID-19 pandemic positively contributed to digital health advancement, especially in developing countries. The fields of artificial intelligence and telehealth (online/phone diagnosis and treatment) have been the most progressive ones (2, 3). All of the digital health advances are directly leading to the improvement of healthcare quality and then longevity. Despite their potential, the use of digital health technology in clinical care and research still faces significant data quality, privacy, and regulatory concerns. 

The near future of pharmaceuticals and supplements

The near future is potentially going to change the type of drugs that we are taking. Instead of drugs treating only a particular disease, we would choose from medicines fighting and preventing multiple diseases at once and slowing down aging. Many of these anti-aging drugs called geroprotectors are already in various clinical trial phases whose status can be checked at the Rejuvenation Roadmap platform. An example of such drugs could be senolytics such as dasatinib with quercetin which target senescent cells and induce cell death. A potential drug for senescent cell therapy is fisetin in the phase 2 study at Mayo Clinic. The other category is calorie restriction mimetics, which imitate the state of caloric restriction in the body by activating AMP protein kinase, inhibiting the mTOR pathway, or activating the sirtuin pathway. The most researched calorie restriction mimetic is metformin which is a hypoglycemic medication for type 2 diabetes. Metformin reduces the prevalence of age-related diseases such as neurodegenerative diseases and cancer. However, the mechanisms by which metformin slows down aging remain largely unknown (4-7). There are also longevity dietary supplements that are intensively researched at the moment, two of which are NAD+ precursors NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside). NAD+ is linked to oxidative stress DNA repair and inflammation, and its levels drop with age.  NMN and NR are known to increase NAD+ amounts, which can improve the function of mitochondria (8).

Most geroprotectors are still found by screening compounds in model organisms, which means little data is available in humans. Recently, the way of searching for potential geroprotective drugs is changing, and new data-driven strategies such as network biology are becoming more common. Thanks to DNA microarrays, next-generation sequencing, and mass spectrometry, an incredible amount of genomic, proteomic, and metabolomic data is available. Network biology uses this data in computational approaches to study the molecular interactions in biological systems (9). The first such tool for geroprotectors search by in silico screening was GeroScope reported in 2016. It uses data of human gene expression differences between young and old adults, compares it to known aging-related signaling pathways, and finds substances that mimic signaling of the young subjects. GeroScope found compounds such as PD-98059, N-acetyl-L-cysteine, Myricetin, and Epigallocatechin gallate that were later tested in vitro in animal models with promising results (10). In 2020 a new strategy called ANDRU (aging network-based drug discovery) to construct a human aging network and identify interventions that can be geroprotective emerged. It differs from GeroScope as it relies on de novo network construction approach. Among the compounds found by ANDRU, type 2 diabetes drugs were identified in this list, including rosiglitazone, pioglitazone, and troglitazone (11). 

Regenerative medicine

Regenerative medicine is an interdisciplinary field that connects engineering and life science inventions to promote the regeneration of injured tissues and organs. Few regenerative medicine therapies and products such as Dermagraft used for diabetic ulcers or Carticel cartilage therapy are already commercially available. Nevertheless, the field is rapidly progressing and could be essential for longevity medicine of the future. 

Tissues and organs used in transplantations mostly come from donors and are often rejected by the patient's immune system. To prevent this and keep the organ architecture, a decellularization approach was discovered. Decellularization (removal of immunogenic cells of the donor organ) captures the organ's structure and material composition and removes the donor antigens. Decellularized organs can be recellurarized before transplantation with the patient's cells, preventing organ rejection. Acellular biological scaffolds are already used on the market as a medical device in quadriceps femoris muscle defects. Another approach is producing entirely artificial scaffolds instead of decellularization. These scaffolds can be prepared from natural purified extracellular matrix components or alginate or synthetic polymers and are researched to help with vascular grafts or mimic lymph nodes. Medical imaging can be used to produce scaffolds closely resembling the patient organ structure (12).

3D bioprinting techniques such as inkjet and microextrusion are new and fascinating ways to restore the structure or function of tissues or organs and could be used instead of classical transplantation. This technology could create more robust tissues and organs for those who await organ transplants that would not be rejected (12). 3D bioprinting is based on the precise positioning of biomaterials and cells in layers replicating the architecture of the replacing tissue or object. Currently, 3D bioprinting of the myocardium is being researched, which could be a breakthrough in cardiology (13).

Stem cell therapies

Stem cells can self-renew and divide while keeping their stemness - the capacity to differentiate into all somatic tissue types. Stem cells are derived from many tissues, even from adult humans, and their use is researched in regenerative medicine, reconstructive surgery, and tissue bioengineering. Stem cells derived from human embryos can maintain stemness and grow for one year or more in a culture which is their main potential. However, their use raises ethical concerns and concerns of rejection reactions in non-related donors. Stem cells could be harvested also from the umbilical cord blood and placenta. This type of cells can be stored in cord blood banks and later used which overcomes the ethical and compatibility concerns. Induced pluripotent stem cells (iPS) derived from modified differentiated adult somatic cells could be more acceptable as they are similar to embryonic stem cells. However, they involve major genetic modifications in in vitro conditions before being used for research and clinical practice, which is a costly procedure. 

Stem cells have the ability to exhibit telomerase activity, renewal, and differentiation. By replacing necrotic or apoptotic cells with healthy ones, they can help regenerate aged tissues and organs. Stem cells when administered can have anti-inflammatory and antiapoptotic properties thanks to paracrine-secreting growth factors and cytokines. Currently, autologous adipose-derived stem cells are the most promising for use in regenerative medicine and anti-aging. They can be harvested in large quantities with minimally invasive liposuction and from a patient. This type of stem cells are safe and effective in preclinical and clinical studies (14-17).

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Gene therapies

Gene therapies are quickly becoming a promising solution for inherited and acquired diseases in humans such as hemophilia, muscular dystrophy, eye and neurodegenerative disorders, and lymphoid cancers. Some of the therapies already got the approved drug status, and many are in the final stages of clinical trials. Gene therapy can treat both somatic and reproductive cells genes. The field has chosen to focus on somatic tissues as gene editing of gametes risks unintended genetic lesions being introduced into the human gene pool. Genes used in gene therapy are introduced into the patient's cells using a vector such as retroviruses and adeno-associated viruses. The virus can transfer the DNA into the cell where the DNA is expressed, creating a treatment. The therapies can be divided into a few types:

• Gene augmentation therapy which introduces to the cell the DNA containing a functional version of the lost gene that causes the disease such as cystic fibrosis.
• Gene inhibition therapy is able to treat infectious diseases, cancer, and diseases caused by faulty gene activity. In this therapy, a DNA fragment is introduced that inhibits the expression of another gene or blocks the activity of its product.
• Specific cell type elimination therapy with potential for diseases such as cancer. The aim here is to insert DNA into a diseased cell that causes that cell to die.
  

Gene therapies have been initially very promising as a treatment that, while implemented, might achieve durable cures without repetition of the therapy. Unlike the protein-based drugs, which often require repeated administration, the gene-based therapies might be enough to lead to a sustainable production of endogenous proteins, such as clotting factors in hemophilia. Initially, the gene therapies have been seen as a treatment for inherited disorders only. But they are now being applied to acquired conditions e.g., genetic engineering of T cells for cancer immunotherapy. Current clinical studies have proven that single infusions of T cells engineered with synthetic genes encoding a chimeric antigen receptor can produce durable responses in a subset of patients. Several genes and gene-modified cell-based therapies are already approved drugs. Over a dozen others have earned "breakthrough therapy" designation. Gene therapies still face a lot of challenges. The gene has to be delivered in the correct tissues and be correctly switched on. Gene therapies have to be designed not to cause an adverse immune system response and would not interfere with the proper working genes in the cell. The crucial limitation in gene therapy is also the cost (18-20).

What is the real near-future?

All of the therapies and advancements listed in this review bring promising news every day. The near-future of longevity medicine would be the implementation of digital health advances first in hospitals and clinics. Secondly, with the progress of machine learning and artificial intelligence, information technology is going to follow. The therapies research will slowly but surely gain pace, which will prolong the lives of thousands of patients.

References

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