2. Longevity Science Basics

2.1 Hallmarks Of Aging

The hallmarks of aging are a group of biological processes that are believed to be responsible for the aging process3. Longevity medicine differs from traditional medicine in that it seeks to address these processes and aging as a whole, instead of treating individual age-related diseases. This is because age-related diseases often share common underlying mechanisms, such as inflammation, cellular damage, and DNA damage, which can be tackled by targeting the aging process itself. By slowing or reversing aging, it may be possible to prevent or delay the onset of multiple age-related diseases simultaneously, rather than dealing with them one by one as they arise.

Nine original hallmarks of aging were first proposed in 2013 by 5 very well respected  researchers in the field and have been widely accepted, making this publication the most highly cited one in the field of aging research. In 2023, 10 years later, a follow up paper was released expanding on the 9 hallmarks and adding 3 more4.

3 https://www.cell.com/fulltext/S0092-8674(13)00645-4
4 https://www.cell.com/cell/pdf/S0092-8674(22)01377-0

2.2.1. Original Hallmarks:

Genomic instability: Damage to the DNA can lead to mutations and other genetic changes. This damage can occur through a variety of mechanisms, including exposure to environmental toxins, radiation, and normal cellular processes like DNA replication. Over time, genomic instability affects aging by contributing to the accumulation of mutations in cells over time. These mutations can affect the function of genes that are critical for cellular processes like DNA repair, cell division, and apoptosis (programmed cell death). As these processes become less efficient, cellular function declines, and the risk of cellular dysfunction and disease increases.

Telomere attrition: Gradual shortening of the protective caps on the ends of chromosomes, called telomeres, occurs with each cell division. This shortening contributes to cellular aging and death. Telomere attrition is thought to be one of the primary mechanisms of aging at the cellular level. As telomeres shorten, cells become less able to divide and replicate, leading to a decline in tissue function and an increased risk of age-related diseases. Short telomeres are also associated with increased inflammation and oxidative stress, which can further contribute to cellular damage and aging.

Epigenetic alterations: Epigenetic alterations refer to changes in the chemical tags on DNA that regulate gene expression. These changes can accumulate over time and contribute to aging. For example, changes in DNA methylation patterns have been associated with age-related changes in gene expression, as well as an increased risk of age-related diseases like cancer and neurodegenerative diseases. 

Epigenetic alterations can be caused by a variety of factors, including environmental exposures and normal cellular processes. As we age, the accumulation of these alterations can lead to changes in gene expression that contribute to cellular dysfunction and aging.

Loss of proteostasis: Proteostasis is a complex system of cellular processes that maintain proper protein folding, degradation, and clearance. The loss of proteostasis with aging is characterized by an accumulation of damaged or misfolded proteins that can contribute to cellular dysfunction and aging. As we age, the proteostasis network becomes less efficient, leading to an increased risk of protein misfolding and aggregation. These aggregates can contribute to a variety of age-related diseases, including Alzheimer's disease and Parkinson's disease.

Dysregulated nutrient sensing: Changes in the cellular pathways that sense and respond to nutrients, such as glucose and amino acids, is known as dysregulated nutrient sensing. These changes can occur with aging and contribute to metabolic dysfunction and an increased risk of age-related diseases like type 2 diabetes and cardiovascular disease.

In particular, dysregulated nutrient sensing can lead to the activation of certain cellular pathways, such as the mTOR pathway, that are associated with cellular aging and disease. These pathways can also contribute to the accumulation of damaged proteins and other cellular components that contribute to aging.

Mitochondrial dysfunction: Mitochondria are the organelles responsible for producing energy in cells (aka the powerhouses of the cell). With aging, there is an accumulation of mitochondrial damage and dysfunction, which can contribute to cellular dysfunction and aging. Mitochondrial dysfunction is associated with a variety of age-related diseases, including neurodegenerative diseases, cardiovascular disease, and metabolic disorders. This dysfunction can lead to decreased energy production, increased production of reactive oxygen species, and impaired cellular signaling, all of which can contribute to aging and disease.

Cellular senescence: Cellular senescence refers to the process by which cells stop dividing and become irreversibly arrested in a state of growth arrest. With aging, there is an accumulation of senescent cells, which can contribute to age-related diseases and impair tissue function. Senescent cells secrete a variety of factors, collectively known as the senescence-associated secretory phenotype (SASP), which can promote inflammation and tissue damage. These factors can contribute to a variety of age-related diseases, including cancer, cardiovascular disease, and neurodegenerative diseases.

Stem cell exhaustion: There is a marked decline in the number and function of stem cells with aging. Stem cells are responsible for repairing and regenerating tissues throughout the body, and as they become depleted or dysfunctional, tissue function declines.

As we age, stem cells become less able to divide and differentiate into the specialized cell types needed for tissue repair and regeneration. This can lead to a decline in tissue function and an increased risk of age-related diseases, such as cardiovascular disease and neurodegenerative diseases.

Altered intercellular communication: Cellular communication changes with aging. This can include changes in the production, secretion, and reception of signaling molecules, such as hormones, cytokines, and growth factors.

These changes in intercellular communication can lead to chronic inflammation, impaired immune function, and other age-related diseases. For example, altered communication between immune cells can lead to chronic inflammation, which is associated with many age-related diseases, including cardiovascular disease, diabetes, and Alzheimer's disease.

2.2.2. New Hallmarks

Disabled macroautophagy: Macroautophagy is a process by which cells degrade and recycle damaged or unwanted cellular components. With aging, there is a decline in the activity of macroautophagy, which can lead to the accumulation of damaged cellular components and impaired cellular function. This impaired macroautophagy can lead to the accumulation of damaged proteins, organelles, and other cellular components, which can contribute to aging and age-related diseases. For example, the accumulation of damaged proteins is associated with neurodegenerative diseases like Alzheimer's and Parkinson's.

Chronic inflammation: A low-level, persistent inflammatory state occurs in the body with aging. This chronic inflammation can be caused by a variety of factors, including cellular damage, infections, and changes in the gut microbiome.

This chronic inflammation is associated with a variety of age-related diseases, including cardiovascular disease, diabetes, and neurodegenerative diseases. The exact mechanisms by which chronic inflammation contributes to these diseases are still being studied, but it is thought to involve the production of inflammatory molecules that damage cells and tissues throughout the body.

Dysbiosis: Dysbiosis is an imbalance in the gut microbiome, which can occur with aging. This imbalance can lead to a decrease in beneficial bacteria and an increase in harmful bacteria, which can result in chronic inflammation and other negative health effects.

Dysbiosis has been linked to a variety of age-related diseases, including inflammatory bowel disease, type 2 diabetes, and even neurodegenerative diseases like Alzheimer's. In addition, dysbiosis can lead to malnutrition and other negative effects on the body's immune system.

These hallmarks of aging are interconnected and all contribute to the complex process of aging. Understanding these processes and developing interventions to address them is an important area of research in the field of aging.

2.2 Where Are We With The Science? 

The science of aging and longevity is a rapidly evolving field, and there have been many exciting developments in recent years. Here are some key areas of progress:

Understanding the biological mechanisms of aging: Scientists have made significant progress in understanding the cellular and molecular mechanisms that contribute to aging, such as cellular senescence, epigenetic regulation, and DNA damage. This knowledge is crucial for developing interventions that target these mechanisms.

Identification of potential interventions: Researchers have identified a number of potential interventions for extending lifespan and promoting healthy aging, such as caloric restriction, intermittent fasting, and exercise. Other promising interventions include senolytic drugs that can clear senescent cells, and compounds that target the mTOR pathway, such as rapamycin.

Advancements in regenerative medicine: The field of regenerative medicine has made remarkable progress in recent years, with scientists developing techniques for growing replacement organs and tissues using stem cells. This could have significant implications for the treatment of age-related diseases and the extension of healthy lifespan.

Precision medicine approaches: Scientists are beginning to use precision medicine approaches to identify individuals who are at high risk for age-related diseases and to develop personalized interventions that are tailored to their unique genetic and environmental profiles.

While there have been significant advancements in the science of aging and longevity, there are still areas where research is lacking or needs further exploration. Here are some examples:

Lack of consensus on biomarkers of aging: There is still no consensus on which biomarkers are the most reliable indicators of biological age or predictors of health outcomes in aging populations. Developing more accurate and reliable biomarkers of aging could help identify individuals at higher risk for age-related diseases and guide interventions to promote healthy aging.

Lack of standardization in intervention studies: There is a lack of standardization in intervention studies on aging and longevity, meaning different studies may use different methods and measures to evaluate the same intervention, making it difficult to compare and evaluate the efficacy of different interventions. More standardized study protocols and outcome measures are needed to improve the quality and rigor of intervention studies.

Insufficient funding: Despite the potential benefits of research on aging and longevity, funding for this field remains relatively low compared to other areas of biomedical research. Increased funding could accelerate progress in this field and help to develop more effective interventions for healthy aging.

2.3 Biomarkers of Longevity - Measuring the Progress Towards Rejuvenation

Biomarkers of longevity are important tools for measuring the progress towards rejuvenation, which refers to the reversal or delay of age-related declines in physical and cognitive function. These biomarkers would be critical in the process of testing therapeutic interventions aimed at extending healthy lifespan as they are measurements one can take in the process indicating changes in key processes. This is necessary because otherwise clinical trials with lifespan as an endpoint would not be viable due to an unmanageable timeframe. Biomarkers can be used to track the effectiveness and stratify clinical trial populations of interventions aimed at promoting healthy aging, allowing researchers and healthcare providers to monitor changes in biological age and functional status over time.

There are several categories of biomarkers that have been identified as potential indicators of biological age or predictors of health outcomes in aging populations. These include molecular biomarkers, such as DNA methylation patterns or telomere length, as well as physiological and functional biomarkers and frailty indexes, such as grip strength, lung capacity, and cognitive function.

It is important to note that no single biomarker can accurately predict longevity or the effectiveness of rejuvenation therapies. Rather, a combination of biomarkers, along with other clinical and lifestyle factors, must be taken into account to provide a comprehensive assessment of an individual's health and functional status.

2.4 Case Studies 

2.4.1 Verve Therapeutics - CRISPR (atherosclerosis)

Verve therapeutics is at the forefront in gene editing. CRISPR is a Nobel Prize winning approach to gene editing that is ushering in a new therapeutic modality where individual ‘faulty’ genes can be precisely corrected. This is opposed to traditional drugs in pill form which are less specific in hitting their gene target, which can lead to significant side effects. Verve is going after one of the most widely validated areas of longevity metabolism - cholesterol. Lowering cholesterol using statins has been one of the most successful therapies to date in all of medicine. It has contributed significantly to lowering mortality due to the #1 cause of mortality, heart disease. They are also associated with a range of other health benefits beyond the cardiovascular system. However, statins have several issues. They can have painful side effects and one has to take a pill every day otherwise one’s cholesterol levels will re-elevate. In contrast, gene editing technology such as that offered by Verve is showing itself to have “one-and-done” potential. In testing in primates, which is needed before testing in humans, with one dose Verve can lower cholesterol by ~60% sustainably for 6-12 months. Verve is currently in human trials. It’s exciting that we won’t have to wait too much longer to see how the first wave of gene editing does. Verve entered clinical trials in New Zealand in 2022, injecting their first trial patient with a “once and done” treatment for correcting high cholesterol levels.

2.4.2 Turn Bio - mRNA (dermatology)

RNA Therapeutics have been in the works for many years, however, the mass production of mRNA vaccines to tackle the COVID-19 pandemic has helped facilitate the development and acceptance of this technology. VitaDAO funded Turn Biotechnologies with $1M as part of their $10M equity fundraising round, alongside Astellas Pharma and Khosla Ventures. It is the first company to focus on transient cellular reprogramming to rejuvenate humans, using mRNA medicines. The goal is to induce the body to heal itself by instructing specific cells to fight disease and repair damaged tissue. Turn.bio is reprogramming the epigenome – a network of chemical compounds and proteins that control cell functions - in order to restore capabilities that are lost with age. Turn Bio have numerous products in their pipeline, including dermatological interventions for skin rejuvenation, wound healing and restoration of follicles to allow new hair growth. They are also aiming to restore protective cartilage, rejuvenate T cells to aid in preventing cellular exhaustion for CAR-T therapies, as well as an ophthalmological medicine to tackle glaucoma. 

2.4.3 CAR-T/CAR-NK tech (cancers and autophagy)
Cell-based therapies are considered the next generation of therapeutics for a multitude of conditions and involve using living cells to treat diseases or injuries. Chimeric antigen receptor (CAR) therapy is the most advanced type and has produced remarkably effective and durable clinical responses in cancer. CARs are engineered synthetic receptors that redirect immune cells, like T and NK cells, to recognize and eliminate abnormal cells expressing a specific target antigen or biomarker. The unprecedented success of CAR-T cell therapy against B cell malignancies directed towards CD19 has resulted in FDA approvals and has led to complete cures in patients. Beyond cancer, many researchers are investigating CAR-based treatments for autoimmune diseases and ageing. In late 2022, the first positive clinical results indicated CAR treatments might be viable for Lupus. Furthermore, VitaDAO has invested in a new project, ApoptoSENS, which is developing CAR-based treatments for ageing disease by targeting senescent cells.

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3. Overcoming the Barriers to Progress
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