25 Longevity Genes You Should Know

Lookin’ Good in Your Genes!

Two weeks ago, we discussed epigenetics, the heritable traits of genes whose mechanistic changes do not directly affect genes themselves. While genes are fixed descriptions of biological systems, epigenetics might be said to be expressions of those descriptions that have a profound impact on our health and subsequent life outcomes. But what exactly are genes, and what types of genes exist?

Genes are segments, or “sequences,” of DNA containing instructions for producing proteins. Each gene corresponds to a specific set of instructions, usually coding for a particular protein or for a particular function. Genes are considered the “basic units of heredity” in living organisms, via passing of characters or traits from parents to offspring through sexual or asexual reproduction. The human genome is said to contain ~20,000 genes.

Over the years, genetic studies have identified a host of genes—dubbed the “longevity genes”—that appear to play central roles in regulating lifespan, healthspan, and aging processes. By tracing the history of our knowledge and our present understanding of these genes, we might be on the brink of unlocking the mysteries of longer, healthier lives. For instance, centenarians are said to have certain “longevity genes” that allow them to fight off chronic disease easier than their contemporaries, or at least with more success. 

Our journey into the realm of longevity genes began with simple model organisms. The nematode C. elegans became the poster child for aging studies, when alterations in genes like DAF-16 and DAF-2 were observed to dramatically affect its lifespan. As research expanded, analogous genes began to emerge in more complex organisms, including mammals, suggesting the potential universality of certain lifespan-regulating mechanisms.

25 Human Genes That Affect Aging and Disease

This week, I decided to create an unordered list in lieu of a long form article. The list is fairly technical, so I reduced each definition down to 2-3 sentences. This felt fitting for the layperson without compromising our education. The idea is to create a quick look at some of the most discussed known genes, whose implications have become talking points of many a longevity researcher. 

Here are 25 genes identified as promoting longevity in humans:

1. APOE: The APOE gene is instrumental in cholesterol regulation. Its roles in platelet aggregability, lymphocyte proliferation, and pathogenesis render it a prime candidate in studies related to atherosclerosis and Alzheimer’s disease. The implications are vast; understanding APOE might help in devising preventive measures for these conditions.

2. P53: Often dubbed the “guardian of the genome,” P53 is pivotal for cellular regulation and the prevention of cancer. When P53 functions are compromised, cells can become susceptible to malignant transformations.

3. SIRT1-7: This gene is deeply involved in metabolism and the response to DNA damage. With its diverse roles, SIRT1 is implicated in aging, cancer, and even lipid metabolism. In essence, it acts as a cellular watchdog, ensuring processes remain balanced.

4. DAF-16: This transcription factor is essential for processes such as cell cycle regulation, apoptosis, and even cellular metabolism. In many ways, it acts as a cellular gatekeeper.

5. CHRNA3: Beyond its association with addictions (to substances like nicotine and alcohol), CHRNA3 plays a foundational role in our nervous system. Its malfunctions can lead to decreased nerve responses, potentially influencing neurological health.

6. SH2B3: As a multifunctional adaptor protein, SH2B3 has implications in several processes. From its involvement in cancer to its role in age-related insulin resistance, understanding SH2B3 could offer therapeutic opportunities.

7. CDKN2A: Central to cell cycle control, this gene, when dysregulated, is implicated in a range of conditions from diabetes type 2 and obesity to cardiac dystrophy. Therapies targeting CDKN2A could potentially stave off these conditions.

8. ELOVL2: This gene is pivotal for fatty acid synthesis, especially for the essential fatty acid DHA. Its significance in lipid storage also ties it to cellular health and response to stress.

9. WRN: The Werner protein is a guardian of our DNA, protecting it against oxidative stress. Its ties to aging are profound, with mutations leading to conditions like premature aging, cataracts, and osteoporosis.

10. PON1: Acting as a detoxifying agent, PON1 significantly reduces chances of atherosclerosis, directly influencing cardiovascular health.

11. SOD2 (Superoxide dismutase 2): This gene plays a critical role in combating oxidative stress. As a ROS scavenger, it helps maintain cellular health and balance. Dysregulation in SOD2 has been associated with conditions like Alzheimer’s disease, diabetes, and cardiac complications.

12. LMNA (Lamin A protein): Essential for the regulation of antioxidant-associated genes, this gene also has a role in cardiac functions. Impairments in LMNA can lead to an accelerated aging process and can disrupt proper protein regulation.

13. CETP (Cholesteryl ester transfer protein): CETP is central to lipoprotein metabolism. Its role has implications for cardiovascular health, with abnormalities associated with various cardiovascular diseases.

14. APOC3 (Apolipoprotein C3): This gene plays multifaceted roles in lipid transport, glucose metabolism, and neuronal signaling. Dysfunctions in APOC3 can lead to insulin resistance, coronary artery complications, and Alzheimer's disease.

15. MTP (Microsomal triglyceride transfer protein): MTP's primary roles revolve around cholesterol synthesis and lipid transport. Ensuring its proper functioning is vital for lipid and lipoprotein homeostasis, and disruptions can pave the way for various metabolic diseases.

16. PIK3CA (Phosphatidylinositol 3-kinase, PI3K): This gene is central to neuronal differentiation and survival. Its dysregulation has been observed in various types of cancers, suggesting its importance in cellular growth and division processes.

17. DAF-2 (Insulin-like growth factor 1, IGF-1 receptor): Recognized for its anabolic and mitogenic activities, this gene plays a significant role in cell growth and division. Alterations in DAF-2 are associated with cancer progression.

18. mTOR (Mechanistic Target of Rapamycin): A serine/threonine protein kinase that plays a central role in cell growth and metabolism by regulating various cellular processes. Its activity and signaling pathways are crucial for many physiological and pathological processes, making it a focal point for research in cancer, aging, and other diseases.

19. GH1 (Growth hormone): As the name suggests, GH1 is vital for growth and development. Its interactions with insulin-like growth factors influence multiple physiological processes. Dysregulation has implications for aging and chronic kidney disease.

20. KLOTHO (Protein alpha-klotho): This intriguing gene is associated with aging suppression. Its roles in organ protection, phosphate homeostasis, and vascular physiology are profound. Dysfunctions in KLOTHO can lead to chronic kidney and vascular diseases.

21. CREB (cAMP-response element binding protein): Essential for neuronal protection, plasticity, and memory, this gene also plays a role in triglyceride metabolism. Abnormalities in CREB can be a precursor to Alzheimer’s disease.

22. MAPK (Mitogen-activated protein kinase): A gene with multiple physiological functions, MAPK is involved in the innate immune response and stress signaling. Its dysregulation has implications for Alzheimer’s disease, Parkinson’s disease, and cardiac hypertrophy.

23. EGFR (epidermal growth factor receptor): Central to nervous system physiology and actin remodeling in sperm capacitation, this gene's malfunctioning can propel cellular growth, leading to cancer.

24. NF-kB (Nuclear factor kappa B): As an immune response modulator and activator, NF-kB plays a significant role in the body's defense mechanisms. However, its dysregulation can lead to depression, coronary artery disease, and other immune diseases.

25. PLC-β (Phospholipase C beta): Engaged in signal transduction and brain activity, this gene has been observed to have roles in breast cancer suppression. Abnormalities in PLC-β can lead to neurodegenerative diseases and metastasis.

Understanding the functions and implications of these genes can provide a roadmap for potential therapeutic interventions and preventive measures, for various health conditions. Each gene, in its unique way, offers insights into the complex tapestry of human physiology and health, and the secret to many centenarians. 

The Benefits of the Basics

Unraveling the intricacies of these genes offers a twofold advantage. Firstly, it shines a light on the genetic architecture underpinning longevity, providing answers to why certain individuals enjoy extended, disease-free lives. Secondly, and perhaps more importantly for many, it unveils potential therapeutic targets. For instance, knowing that a particular gene's malfunction amplifies the risk of a specific disease can guide therapeutic interventions, whether they be drug-based or lifestyle-oriented.

The future of longevity gene research is rife with potential. As genomic technologies evolve and become more accessible, we are likely to see an exponential increase in our understanding. DNA Script, a Paris-based genomics startup, has been developing technology to use enzymes to write DNA. They believe they have created the world’s first “DNA printer powered by enzymatic technology.” Custom DNA from companies like these can revolutionize how researchers approach synthetic biology and other fields that require custom DNA sequences. The introduction of specific mutations, modified nucleotides, or the design of unique DNA structures, might have applications in personalized medicine, where specific DNA sequences can be designed and synthesized based on an individual's genetic makeup for therapeutic or diagnostic purposes.

We may be on the brink of an era where genetic insights offer personalized health recommendations, guiding individuals towards interventions that might extend their healthspan and potentially lifespan.

Horizon

As we continue to uncover the layers of genetic intricacies dictating our lifespan and healthspan, we inch closer to realizing the dream of extended, healthy lives. With each discovery, we rewrite our understanding of human health, paving the way for a future where age might truly be just a number. While our genes do not describe our destinies, we can better understand the road ahead as we understand ourselves. From there, the summit to human longevity should be within walking distance, just before the sunrise.