Super Agers

1. Healthy Aging is About Health Span, Not Just Lifespan.

What we really want is for the additional years of life to be essentially free from disease.

Focus on quality. The true goal isn't merely extending the number of years we live (lifespan), but maximizing the years lived in optimal health, free from chronic disease and disability (health span). While longevity is desirable, living longer with conditions like Alzheimer's or severe frailty is not ideal. The shift from being "Illderly" to staying "Wellderly" is the core aspiration.

Current reality. In the United States, a significant majority of older adults suffer from multiple chronic diseases. For those aged 65 and older, 80% have two or more conditions, and about 7% have five or more. This highlights the current gap between lifespan and health span, a gap that is unfortunately widening.

Future potential. The good news is that maximizing healthy years is becoming increasingly attainable. Breakthroughs in science and technology are paving the way to prevent or significantly delay age-related diseases, offering the promise that the second half of our lives can be much healthier than that of our ancestors.

2. A Revolution in Health Span is Driven by Five Converging Dimensions.

This multidimensional revolution in health span has been powered by a convergence of breakthroughs in life science and information technology.

Five key areas. The unprecedented progress in extending healthy life is fueled by simultaneous advancements across five interconnected dimensions: Lifestyle+, Cells, Omics, Artificial Intelligence (AI), and Drugs/Vaccines. These areas interact and amplify each other, creating powerful new possibilities.

Interconnected progress. Breakthroughs in one dimension often enable progress in others. For example:

• Omics data (like genomics) informs personalized Lifestyle+ recommendations.
• AI integrates data from all dimensions to improve medical forecasting.
• Cell engineering allows for new types of "living drugs."
• AI accelerates the discovery of new Drugs and Vaccines.

Historic convergence. This moment is unique because decades of foundational research in areas like genome sequencing, CRISPR, mRNA technology, and AI are now converging. This collective effort puts us in a position to fundamentally reset our expectations for human health span.

3. Lifestyle+ (Diet, Exercise, Sleep, Environment) is the Foundational Pillar of Healthy Aging.

Many more healthy years can be added to our lives without fancy, expensive technology.

Beyond the basics. Lifestyle+ expands the traditional focus on diet, exercise, and sleep to include environmental factors like pollution, microplastics, and social determinants of health such as loneliness. These factors collectively have a profound impact on health span.

Diet matters. Poor diet is linked to 22% of all deaths globally. Avoiding ultra-processed foods (UPFs) with their harmful additives and physical structures is crucial, as UPFs are associated with increased risks of cardiovascular, metabolic, cognitive, and other diseases. Limiting sugary beverages and being mindful of salt intake are also important.

Exercise is medicine. Regular physical activity is arguably the single most effective medical intervention known. It benefits nearly every organ system, reducing risks of cardiovascular disease, cancer, neurodegeneration, and improving mental health. Combining aerobic exercise with strength and balance training is key, and it's never too late to start. Sleep is equally vital for brain health, waste clearance, and overall well-being, with around seven hours being optimal for most adults.

4. Cardiovascular Disease: Prevention is Key Through Early Detection and Targeted Care.

It is indeed the most preventable of the chronic killers discussed in this part of the book.

Still the leading cause. Despite significant progress, cardiovascular disease remains the number one killer globally and is unfortunately on the rise again in the US. The primary driver is atherosclerosis, the buildup of plaque in arteries, a process that begins decades before symptoms appear.

Early detection tools. We now have powerful tools to identify individuals at high risk long before a heart attack or stroke occurs. These include:

• Polygenic risk scores (genetic predisposition)
• Proteomic scores (blood protein profiles)
• AI analysis of medical images (retina, chest X-ray)
• Biomarkers of inflammation (hs-CRP)
• Clonal hematopoiesis (CHIP)

Targeted interventions. Knowing who is at high risk allows for aggressive primary prevention. This involves optimizing lifestyle+ factors, managing traditional risks like blood pressure and lipids (with potent statins and new drugs like PCSK9 inhibitors), and increasingly, targeting inflammation with drugs like colchicine. This proactive approach aims to prevent the disease from ever manifesting.

5. Metabolic Health: Tackling Obesity and Diabetes is Crucial, Aided by Breakthrough Drugs.

This breakthrough family of drugs, and future derivatives such as the pills, like orforglipron, or even a vaccine-like version, have extraordinary potential to promote health span beyond what they have already accomplished.

The diabesity epidemic. Obesity and type 2 diabetes are twin pandemics driving a wide range of chronic diseases, including heart, kidney, liver, and neurodegenerative conditions. While often linked, type 2 diabetes has distinct genetic underpinnings and can occur independently of obesity.

GLP-1 breakthrough. The GLP-1 family of drugs (like Ozempic, Wegovy, Mounjaro, Zepbound) represents a monumental achievement, offering unprecedented weight loss and significant benefits for cardiovascular and kidney disease. These drugs work through complex mechanisms involving gut hormones and brain pathways, reducing appetite, improving insulin sensitivity, and suppressing inflammation.

Beyond weight loss. GLP-1 drugs show promise for treating sleep apnea, fatty liver disease, and potentially even neurodegenerative conditions like Parkinson's and Alzheimer's. However, challenges remain, including side effects, the potential need for lifelong use, high cost, and exacerbating health inequities. Addressing metabolic health requires a multi-faceted approach combining lifestyle, genetics, and targeted therapies.

6. Cancer: Shifting from Mass Screening to Personalized Risk Detection and Targeted Treatment.

We know so much about cancer now that we can transform the practice of medicine, and much of that knowledge is ready for you to use.

Rising incidence. Cancer incidence is increasing, particularly in younger populations, defying traditional age-based patterns. Current mass screening methods are inefficient, expensive, and often detect cancers at later stages. The goal is to detect cancer early, ideally before it spreads, as metastasis is the primary cause of death.

Personalized risk assessment. The future of cancer detection lies in identifying high-risk individuals through integrating multiple data layers:

• Polygenic risk scores and genome sequencing
• AI analysis of electronic health records and medical images
• Emerging blood biomarkers (e.g., cell-free tumor DNA, proteins)

Targeted therapies. Treatment is moving away from non-specific chemotherapy towards highly targeted approaches based on a tumor's molecular characteristics. Breakthroughs include:

• Antibody-drug conjugates (weaponized antibodies)
• Immunotherapies (checkpoint inhibitors, BiTEs)
• Cancer vaccines (personalized neoantigen vaccines)
• Engineered cell therapies (CAR-T cells)

These innovations leverage the power of the immune system and precision targeting to fight cancer more effectively and with fewer side effects, offering hope for improved outcomes and prevention strategies.

7. Neurodegeneration: Early Biomarkers and Lifestyle Offer Hope Against Brain Aging.

Knowing that it takes decades for the development of Alzheimer’s disease in concert with its prelude of cognitive impairment, there has long been a search for some sign that the disease is coming, a biomarker.

Brain aging is complex. Neurodegenerative diseases like Alzheimer's and Parkinson's are characterized by protein accumulation, inflammation, and brain cell death, processes that unfold over decades. The brain's immune system, particularly microglia, plays a key role. Structural changes occur with age, but individual trajectories vary.

Biomarker breakthroughs. Significant progress has been made in identifying early signs of these diseases:

• Blood tests for phosphorylated tau (p-tau217) for Alzheimer's
• Alpha-synuclein seed amplification assays (SAA) for Parkinson's
• Plasma protein panels and AI analysis of retinal images for prediction

Lifestyle impact. Lifestyle+ factors are crucial for brain health. Exercise promotes neurogenesis and reduces inflammation. Sleep is essential for waste clearance. Diet, social connection, and environmental factors also play significant roles. Up to half of dementia cases may be preventable or significantly delayed through modifiable risks.

While current drug treatments for established Alzheimer's show only modest benefits with significant risks, the focus is shifting to prevention in high-risk individuals using biomarkers, lifestyle interventions, and promising new drug targets or gene therapies.

8. Controlling the Immune System Unlocks Prevention and Cures for Autoimmune Diseases.

About eighty different autoimmune diseases affect more than 10 percent of the population.

Immune system gone awry. Autoimmune diseases occur when the body's immune system mistakenly attacks its own tissues. These conditions are common, often chronic, and currently managed with broad immunosuppression, which carries risks and is not curative.

Restoring tolerance. The goal is to restore immune tolerance, teaching the immune system to ignore self-antigens. Exciting new strategies are emerging:

• Tolerogenic nanoparticles loaded with antigens to generate regulatory T cells (Tregs)
• Glycosylated antigens delivered to the liver to induce tolerance
• Inverse vaccines that deactivate specific immune responses
• Engineered cell therapies (e.g., CAR-T targeting B cells) to reset the immune system

Gut microbiome role. The gut microbiome is a central regulator of the immune system. Its composition is altered in autoimmune conditions, and manipulating it through prebiotics, probiotics, or fecal transplants shows promise as an anti-inflammatory or tolerogenic approach.

These targeted strategies offer hope for more specific, effective, and potentially curative treatments for autoimmune diseases, moving beyond broad immunosuppression.

9. Defeating Infectious Agents: Rapid Advances in Vaccines and Diagnostics Offer New Hope.

It took ten months.

COVID catalyst. The COVID-19 pandemic dramatically accelerated progress in infectious disease control. The rapid development of highly effective mRNA vaccines, built on decades of foundational research (mRNA modification, nanoparticle delivery, structure-based design), was unprecedented.

New vaccine platforms. The mRNA/lipid nanoparticle platform is now being applied to a wide range of pathogens, including influenza (towards a universal vaccine), RSV, malaria, TB, and HIV. Structure-based design is enabling more potent and durable vaccines. However, challenges remain with waning immunity and viral evolution, driving the need for next-generation vaccines (self-amplifying RNA, pan-coronavirus, mucosal).

Advanced diagnostics. Tracking pathogens has been revolutionized by:

• Genomic sequencing of viruses (e.g., SARS-CoV-2 variants)
• Wastewater surveillance to predict outbreaks
• Metagenomic sequencing of patient samples for rapid, unbiased pathogen identification and resistance profiling

These advancements, coupled with AI for prediction and diagnosis (e.g., sepsis), offer powerful new tools to prevent, detect, and treat infectious diseases more effectively, although overcoming anti-science movements remains a significant challenge.

10. Gene Editing and Other 'Omics' Therapies Offer Potential Cures, Starting with Rare Diseases.

At the very least, your children or grandchildren may undergo some form of genome editing during their lifetime.

Beyond rare diseases. While gene editing (CRISPR) and gene therapy are currently approved or in trials for rare genetic disorders (sickle cell anemia, familial hypercholesterolemia), these technologies hold immense potential for treating common age-related diseases by targeting underlying genetic or molecular causes.

Evolution of gene editing. CRISPR technology has rapidly advanced from disruptive gene knockout (CRISPR 1.0) to precise gene fixing (base and prime editing, CRISPR 2.0). Delivery methods are improving, moving towards in vivo (in the body) approaches using nanoparticles or engineered viruses, aiming for one-shot cures.

Expanding omics therapies. Beyond DNA editing, new modalities are emerging:

• RNA editing to alter protein production temporarily
• Epigenetic editing to tune gene expression without changing DNA sequence
• Microbiome editing to modify gut bacteria function
• Mitochondrial editing to address mtDNA mutations

These technologies offer unprecedented precision in manipulating biological processes, opening new avenues for treating diseases at their root cause, although ethical considerations, safety concerns (off-target effects, unintended consequences), and high costs remain significant hurdles.

11. Promoting Mental Health is Interdependent with Physical Health, Aided by Digital Tools.

The complex interactions between our mental and physical health have never been fully broken down, and likely never will be, but there’s no question that they are interdependent.

Holistic health. Mental health is inextricably linked to physical health and is crucial for extending health span. High rates of anxiety, stress, and depression highlight a significant unmet need, exacerbated by a shortage of mental health professionals.

Lifestyle+ impact. Many lifestyle factors profoundly influence mental well-being:

• Time in nature reduces stress, anxiety, and depression.
• Music-based interventions show promise for mood and cognitive function.
• Adequate sleep improves mood and resilience.
• Regular exercise is as effective as or better than medication for depression.
• Social connection combats loneliness and isolation, which are linked to increased mortality and dementia risk.

Digital support. Technology is expanding access to mental health support. Virtual therapy is common, and digital tools are evolving:

• Wearable sensors provide objective data on mood-related metrics.
• Digital cognitive behavioral therapy (dCBT) apps offer scalable, interactive support.
• AI chatbots provide accessible, 24/7 conversational support, showing promise for reducing anxiety and depression.

While digital tools offer convenience and scalability, they are best viewed as adjuncts to human care, and concerns about data privacy and safety require careful attention.

12. Modulating the Aging Process Itself is the Ultimate Goal, But Still a Future Prospect.

There’s no evidence yet for safely and effectively slowing the aging process in human beings.

The ultimate prize. The most ambitious goal is to slow or reverse the biological aging process itself, aiming for a "compression of morbidity" where healthy life is extended with minimal time spent in chronic illness. This is distinct from preventing individual age-related diseases.

Hallmarks of aging. Research has identified twelve biological hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, etc.), each representing a potential target for intervention. Companies are investing heavily in strategies to modulate these hallmarks.

Promising avenues (in research):

• Partial epigenetic reprogramming to reset cellular age
• Senolytics to clear old, dysfunctional cells
• Rejuvenating the immune system
• Targeting nutrient sensing pathways (e.g., mTOR inhibitors like rapamycin)
• Identifying "youth factors" from young blood or CSF

Challenges and risks. Proving anti-aging effects in humans is difficult and requires long-term trials. Many interventions carry risks, particularly the potential to promote cancer, as the hallmarks of aging and cancer are deeply intertwined. Ethical considerations and ensuring equitable access are also major hurdles. While organ-specific aging can be tracked and potentially targeted sooner, body-wide aging modulation remains a distant, albeit exciting, prospect.

Last updated: June 11, 2025