The Geroscience Paradigm: Unraveling the Biological Foundations of Aging to Extend Healthspan

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Geroscience represents a transformative, interdisciplinary field dedicated to elucidating the intricate biological mechanisms that underpin aging and their profound influence on the etiology and progression of a multitude of age-related diseases. Diverging from the traditional disease-specific medical model, geroscience posits that by precisely identifying and therapeutically targeting these fundamental aging mechanisms, it is possible to achieve the simultaneous delay or prevention of numerous chronic conditions. This groundbreaking approach aims to significantly extend healthspan—the invaluable period of life characterized by freedom from debilitating disease and disability—thereby enhancing the quality of life for individuals as they age. This comprehensive report meticulously explores the historical trajectory and foundational theoretical underpinnings that gave rise to geroscience, significantly expands upon its extensive scope far beyond commonly cited examples, delves deeply into the diverse and interconnected hallmarks of aging that serve as its primary research targets, and meticulously details the inherently interdisciplinary nature of the research endeavors within this dynamic field. Crucially, it discusses the profound potential of geroscience to catalyze a monumental shift in medical paradigms, moving decisively from a reactive model of treating individual diseases to a proactive, holistic strategy focused on promoting sustained health by directly addressing the overarching process of aging itself.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Aging, a universal biological process characterized by a progressive decline in physiological integrity, stands as the single most formidable risk factor for a vast array of chronic, debilitating diseases. These include, but are not limited to, prevalent cardiovascular disorders such as atherosclerosis and hypertension; a spectrum of neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases; metabolic dysregulations including type 2 diabetes; musculoskeletal ailments such as osteoporosis and sarcopenia; various forms of cancer; and immune system decline, known as immunosenescence. The societal and economic burden imposed by these age-related conditions is immense, straining healthcare systems globally and significantly diminishing the quality of life for an ever-growing aging population. For decades, the prevailing medical paradigm has primarily focused on a disease-centric approach: diagnosing and treating individual pathologies as they arise, often through pharmacotherapy or surgical interventions designed to manage symptoms or slow disease progression. While undeniably effective in many instances, this traditional model frequently operates downstream of the fundamental biological processes that instigate these diseases, often resulting in a fragmented approach that treats symptoms rather than root causes.

Geroscience proposes a revolutionary paradigm shift. Instead of tackling each age-related disease in isolation, it advocates for targeting the fundamental biological mechanisms of aging that serve as common drivers for multiple pathologies. The central hypothesis is that if these underlying aging processes can be modulated, it will be possible to prevent or delay the onset and progression of a cluster of age-related diseases simultaneously. This integrated approach holds immense promise for not only extending an individual’s total lifespan but, more significantly, for extending their healthspan—the duration of life spent in good health, free from significant disease and disability. By enhancing resilience to chronic disease and promoting functional independence into later life, geroscience seeks to fundamentally redefine the experience of aging, offering a pathway to a future where healthy aging is the norm, not the exception.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Historical Context and Foundational Theories

Understanding the origins and theoretical evolution of geroscience requires a look back at centuries of human inquiry into the nature of aging. The fascination with extending youth and defeating senescence dates back to ancient civilizations, but a scientific approach to aging began to crystallize in the late 19th and early 20th centuries. The term ‘gerontology’ was officially coined in 1903 by Ilya Metchnikoff, a Russian zoologist and Nobel laureate, to describe the scientific study of aging and the problems associated with it, encompassing biological, medical, psychological, and sociological aspects (Metchnikoff, 1903). Early gerontological research often focused on descriptive studies, documenting the physiological changes associated with age across various species and observing demographic trends. However, these early efforts, while foundational, often lacked a unifying theoretical framework to explain why organisms age.

The mid-20th century saw the emergence of several critical biological theories that attempted to explain aging at a mechanistic level. Theories such as the ‘wear and tear’ hypothesis, suggesting that cells and tissues simply break down over time, and the ‘rate of living’ theory, proposing that faster metabolism leads to shorter lifespans, provided initial conceptualizations but were eventually found to be too simplistic to fully account for the complexities of aging. A more profound shift occurred with the development of genetic and evolutionary theories of aging, which laid much of the groundwork for geroscience.

2.1. Evolutionary Theories of Aging

The most influential evolutionary theories, developed in the mid-20th century, profoundly shaped our understanding of aging as a genetically influenced process, rather than simply a byproduct of physical deterioration. These theories explain why natural selection, a powerful force optimizing survival and reproduction, has seemingly allowed aging to persist.

2.1.1. Mutation Accumulation Theory

Proposed by Peter Medawar in 1952, the mutation accumulation theory posits that deleterious mutations that manifest their harmful effects late in life are subject to weak negative selection pressure. This is because, in natural populations, few individuals survive long enough to experience these late-acting mutations, having already reproduced. Therefore, these mutations can accumulate in the genome over evolutionary time, contributing to age-related decline (Medawar, 1952). The strength of this theory lies in explaining the existence of late-life frailty and disease, suggesting that aging is largely an unselected byproduct of insufficient selective pressure against late-acting detrimental genetic variants.

2.1.2. Antagonistic Pleiotropy Theory

Building upon Medawar’s ideas, George C. Williams in 1957 introduced the antagonistic pleiotropy theory, which argues that certain genes may confer significant fitness advantages early in life, promoting survival and reproductive success, but concurrently exert detrimental, deleterious effects later in life (Williams, 1957). These genes are favored by natural selection due to their early-life benefits, even if they contribute to aging and disease in post-reproductive years. A classic hypothetical example is a gene that promotes rapid growth and early maturation, thereby increasing reproductive output, but also increases the risk of cancer in old age. Real-world examples are actively being investigated, with genes like p53 (a tumor suppressor that can also induce senescence) and components of the IGF-1 signaling pathway being potential candidates that exhibit such antagonistic pleiotropic effects. The APOE4 allele, associated with increased risk of Alzheimer’s disease, has also been theorized to have conferred benefits related to pathogen response or cognitive function in ancestral environments, particularly earlier in life (Wolfe et al., 2018).

2.1.3. Disposable Soma Theory

The disposable soma theory, articulated by Thomas Kirkwood in 1977, provides an elegant evolutionary explanation for the trade-off between somatic maintenance and reproduction (Kirkwood, 1977). This theory suggests that organisms face a fundamental allocation dilemma: they have finite resources (energy, nutrients) that must be distributed between maintaining the body (soma) to ensure its survival and investing in reproduction to pass on genetic material. From an evolutionary perspective, there is an optimal investment in maintenance. Beyond a certain point, further investment in somatic repair and longevity yields diminishing returns, as individuals are likely to die from extrinsic causes (predation, accidents, disease) before reaching extreme old age. Consequently, natural selection favors strategies that prioritize reproduction over indefinite somatic maintenance. This leads to an accumulation of unrepaired cellular damage over time, which ultimately manifests as aging. The theory predicts that species with lower extrinsic mortality rates (e.g., bats, naked mole-rats) will evolve more robust maintenance mechanisms and therefore live longer, which is supported by comparative biology.

2.2. Emergence of Geroscience

While gerontology provided a broad framework, the true emergence of geroscience as a distinct, focused discipline occurred in the late 20th and early 21st centuries. This was propelled by revolutionary advancements in molecular biology, genomics, and cellular biology, which enabled scientists to delve into the precise molecular mechanisms underlying age-related changes. Key discoveries included: the identification of specific genes influencing longevity in model organisms (e.g., C. elegans, Drosophila); the elucidation of nutrient-sensing pathways like insulin/IGF-1 signaling (IIS) and mTOR; the recognition of cellular senescence and its role in tissue dysfunction; and a growing understanding of DNA damage and repair processes. These breakthroughs revealed that many age-related diseases shared common mechanistic roots in the aging process itself. The conceptualization of geroscience gained significant traction with the realization that targeting these common pathways could offer a more efficient and impactful strategy for promoting healthy aging than addressing each disease in isolation. The National Institute on Aging (NIA) in the United States played a crucial role in championing this new perspective, recognizing the potential for a ‘longevity dividend’ if aging itself could be targeted (Olshansky et al., 2006).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Scope of Geroscience

Geroscience is characterized by its expansive and multifaceted scope, integrating insights from an unusually broad spectrum of scientific disciplines. This holistic approach is essential because aging is not a monolithic process but rather a complex, multifactorial phenomenon involving intricate interactions across various biological scales. The field goes beyond mere observation to actively dissect the causality and interconnectedness of age-related changes.

3.1. Molecular and Cellular Mechanisms

At the foundational level, geroscience rigorously investigates the myriad molecular and cellular processes that undergo progressive decline and dysregulation with age. These include:

• DNA Repair Mechanisms: The integrity of the genome is constantly challenged by endogenous (e.g., reactive oxygen species, replication errors) and exogenous (e.g., UV radiation, chemical mutagens) stressors. Aging is associated with a decline in the efficiency and fidelity of DNA repair pathways, such as nucleotide excision repair (NER), base excision repair (BER), homologous recombination (HR), and non-homologous end joining (NHEJ). This impaired repair leads to the accumulation of DNA damage, genomic instability, and increased mutation rates, contributing to cancer, neurodegeneration, and cellular dysfunction.

• Protein Folding and Quality Control (Proteostasis): Cells maintain a delicate balance of correctly folded proteins, a process known as proteostasis. With age, the machinery responsible for protein folding (chaperones), degradation (ubiquitin-proteasome system, lysosomes), and refolding becomes less efficient. This leads to the accumulation of misfolded and aggregated proteins, which can be toxic and impair cellular function. Examples include amyloid-beta plaques and tau tangles in Alzheimer’s disease, and alpha-synuclein aggregates in Parkinson’s disease. Impaired proteostasis also triggers the endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR), which can contribute to chronic inflammation and cellular demise.

• Autophagy and Lysosomal Function: Autophagy is a crucial cellular recycling process that degrades and recycles damaged organelles and misfolded proteins. Lysosomes, the ‘recycling centers’ of the cell, are central to this process. Aging is associated with a significant decline in autophagic flux and lysosomal function, leading to the accumulation of cellular waste products (like lipofuscin) and damaged organelles (e.g., dysfunctional mitochondria). Restoring autophagic efficiency is a key therapeutic target in geroscience.

• Mitochondrial Biology: Mitochondria are the primary producers of cellular energy (ATP) through oxidative phosphorylation. They are also a major source of reactive oxygen species (ROS). With aging, mitochondria suffer from increased oxidative damage, mutations in mitochondrial DNA (mtDNA), decreased efficiency of the electron transport chain, and impaired quality control mechanisms like mitophagy (selective degradation of damaged mitochondria). This leads to energy deficits, increased oxidative stress, and cellular dysfunction, profoundly impacting organ systems like the brain, heart, and muscle.

3.2. Genetics and Epigenetics

Genetic predisposition and dynamic epigenetic modifications play critical roles in shaping an individual’s aging trajectory.

• Genetics: Research in model organisms has identified specific genes and pathways that profoundly influence longevity. In humans, genome-wide association studies (GWAS) have pinpointed single nucleotide polymorphisms (SNPs) associated with exceptional longevity or increased risk for age-related diseases. Genes involved in nutrient sensing (e.g., FOXO transcription factors, sirtuins, mTOR pathway components), DNA repair, and immune response have been implicated. Understanding these genetic variants helps identify individuals at higher risk and potential therapeutic targets.

• Epigenetics: Epigenetic modifications are heritable changes in gene expression that occur without altering the underlying DNA sequence. These include DNA methylation, histone modifications (acetylation, methylation, phosphorylation), and chromatin remodeling. With age, significant alterations occur in the epigenome, often leading to global hypomethylation and site-specific hypermethylation, loss of histone acetylation patterns, and overall chromatin decompaction. These ‘epigenetic drift’ changes can silence beneficial genes or activate deleterious ones, contributing to cellular dysfunction and disease. Epigenetic clocks, such as the Horvath clock, measure DNA methylation patterns to provide highly accurate estimates of biological age, often deviating from chronological age, making them powerful biomarkers for aging research (Horvath, 2013).

3.3. Systems Biology

Geroscience employs a systems biology approach to understand how complex interactions among genes, proteins, metabolites, and cells affect aging at the organismal level. This involves:

• Multi-omics Integration: Combining data from genomics, transcriptomics, proteomics, metabolomics, and lipidomics to create a comprehensive picture of age-related changes. This allows for the identification of perturbed pathways and networks that span multiple biological levels.
• Network Analysis and Computational Modeling: Using sophisticated computational tools to map intricate cellular and physiological networks and model how disruptions in these networks contribute to aging phenotypes and disease susceptibility. This helps identify critical nodes and feedback loops that could be targeted therapeutically.
• Inter-organ Communication: Investigating how aging in one organ system (e.g., gut microbiome) can profoundly influence the health and function of distant organs (e.g., brain, immune system). This highlights the systemic nature of aging and the importance of considering whole-body interventions.

3.4. Environmental and Lifestyle Factors

Extrinsic factors significantly modulate the aging process, offering promising avenues for non-pharmacological interventions.

• Dietary Interventions: Caloric restriction (reducing calorie intake without malnutrition) has been consistently shown to extend lifespan and healthspan in diverse model organisms by modulating nutrient-sensing pathways (e.g., mTOR, AMPK, sirtuins). Intermittent fasting and specific dietary patterns (e.g., Mediterranean diet, ketogenic diet) are also under intense investigation for their geroprotective effects. The role of specific macronutrients and micronutrients, as well as the gut microbiome, is a key area of research.
• Exercise: Regular physical activity, encompassing aerobic, resistance, and high-intensity interval training (HIIT), confers numerous anti-aging benefits. Exercise improves cardiovascular health, preserves muscle mass (combating sarcopenia), enhances cognitive function, boosts immune surveillance, and modulates systemic inflammation. At a molecular level, it can stimulate mitochondrial biogenesis, activate AMPK, and improve insulin sensitivity.
• Stress Management: Chronic psychological stress elevates cortisol levels, disrupts the hypothalamic-pituitary-adrenal (HPA) axis, and promotes chronic low-grade inflammation, all of which accelerate biological aging. Mind-body practices, adequate sleep, and social engagement are critical for mitigating these effects.
• Environmental Exposures: Exposure to environmental toxins (e.g., air pollution, heavy metals, pesticides) and lifestyle factors like smoking or excessive alcohol consumption can accelerate cellular damage, epigenetic alterations, and systemic inflammation, thereby contributing to premature aging and increased disease risk.

3.5. Social Determinants of Aging

Geroscience increasingly recognizes that biological aging does not occur in a vacuum but is profoundly shaped by an individual’s social, economic, and environmental context (Crimmins et al., 2020; Pifer et al., 2020). This expanding area investigates how macro-level societal factors translate into micro-level biological changes.

• Socioeconomic Status (SES): Lower SES, often characterized by limited access to quality education, nutritious food, safe housing, and healthcare, is consistently associated with accelerated biological aging, higher rates of chronic disease, and shorter healthspans. Chronic financial stress, job insecurity, and adverse working conditions contribute to increased allostatic load, which can manifest as epigenetic alterations and elevated inflammatory markers.
• Social Isolation and Support Systems: Lack of social connection, loneliness, and inadequate social support are recognized risk factors for poor health outcomes and accelerated aging. Social isolation can induce chronic stress responses, impair immune function, and contribute to cognitive decline.
• Environmental Contexts: Living in disadvantaged neighborhoods with higher exposure to pollution, crime, and fewer green spaces can exacerbate biological aging processes. These exposures can lead to increased oxidative stress and inflammation, with measurable effects on cellular aging markers.
• Psychological Stress and Adversity: Experiences of discrimination, early-life trauma, and chronic psychosocial stress can have long-lasting effects on physiological systems, impacting gene expression, telomere length, and immune function, thereby influencing an individual’s biological age and disease susceptibility throughout life.

These social determinants collectively contribute to ‘social hallmarks of aging,’ which influence and interact with the biological hallmarks, highlighting the need for comprehensive interventions that address both individual biology and broader societal inequities.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Hallmarks of Aging

The conceptual framework of ‘hallmarks of aging,’ first proposed by López-Otín et al. in 2013, revolutionized the field by providing a structured and comprehensive classification of the fundamental biological processes driving aging (López-Otín et al., 2013). This initial framework identified nine interdependent hallmarks, which have since been refined and expanded upon in subsequent research (López-Otín et al., 2023). These hallmarks represent primary damage sources, compensatory responses, and integrative pathologies that collectively drive the aging phenotype and contribute to the susceptibility to age-related diseases. Critically, these hallmarks are not isolated but interact in a complex network, often exacerbating one another. Targeting these hallmarks forms the central strategy of geroscience for therapeutic intervention.

4.1. Primary Hallmarks (Causes of Damage)

These hallmarks represent the initial molecular damage that accumulates over time, often due to intrinsic cellular processes or environmental insults.

4.1.1. Genomic Instability

Description: The progressive accumulation of alterations to the genome, including DNA mutations (point mutations, deletions, insertions), chromosomal rearrangements (translocations, aneuploidy), and changes in copy number, due to impaired DNA repair mechanisms or increased exposure to damaging agents.

Mechanism: DNA damage sources include reactive oxygen species (ROS) from metabolism, replication errors, environmental toxins, and radiation. While cells possess elaborate DNA repair pathways (BER, NER, HR, NHEJ), their efficiency declines with age. This leads to unrepaired or misrepaired damage, resulting in genomic instability. Accumulation of damage in mitochondrial DNA (mtDNA) is particularly relevant for cellular energy production.

Contribution to Aging/Disease: Genomic instability is a well-established driver of cancer by promoting oncogenic mutations. It also contributes to neurodegeneration through neuronal dysfunction and death, and to immunosenescence through impaired lymphocyte function. Defects in DNA repair pathways are linked to premature aging syndromes like Werner syndrome and Cockayne syndrome.

Therapeutic Relevance: Strategies include enhancing DNA repair mechanisms, reducing oxidative stress, and developing compounds that selectively eliminate cells with excessive genomic damage.

4.1.2. Telomere Attrition

Description: Telomeres are protective caps at the ends of chromosomes, composed of repetitive DNA sequences (TTAGGG in mammals) and associated proteins (shelterin complex). They safeguard chromosomal integrity. Due to the ‘end replication problem’ (DNA polymerase cannot fully replicate the very end of a linear chromosome) and oxidative stress, telomeres progressively shorten with each cell division.

Mechanism: Once telomeres reach a critically short length, they are recognized as DNA damage, triggering a DNA damage response that halts cell division and can induce cellular senescence or apoptosis. The enzyme telomerase can elongate telomeres, but its activity is typically repressed in most somatic cells, though active in germline cells and cancer cells.

Contribution to Aging/Disease: Telomere shortening limits the replicative capacity of somatic cells, contributing to replicative senescence, particularly in tissues requiring high turnover (e.g., skin, immune cells, hematopoietic stem cells). Critically short telomeres are associated with bone marrow failure, pulmonary fibrosis, and increased risk of various age-related diseases and overall mortality.

Therapeutic Relevance: Research explores telomerase activators or gene therapies to extend telomere length, though concerns exist regarding potential cancer promotion.

4.1.3. Epigenetic Alterations

Description: Changes in the epigenome—modifications to DNA and histone proteins that affect gene expression without altering the underlying DNA sequence—that accumulate with age.

Mechanism: Key epigenetic marks include DNA methylation (addition of a methyl group to cytosine bases), histone modifications (acetylation, methylation, phosphorylation, ubiquitination of histone tails), and changes in chromatin structure (e.g., heterochromatin loss). Aging leads to a global loss of DNA methylation (hypomethylation) in some regions and gain of methylation (hypermethylation) in others, particularly at CpG islands in promoter regions. Histone modification patterns also become dysregulated, leading to altered gene expression. This ‘epigenetic drift’ disrupts transcriptional fidelity and cellular identity.

Contribution to Aging/Disease: Epigenetic alterations contribute to the dysregulation of gene expression profiles characteristic of aging cells, affecting cell differentiation, metabolism, and stress responses. They are implicated in cancer, neurodegeneration, and metabolic diseases. Epigenetic clocks are highly accurate biomarkers of biological age (Horvath, 2013).

Therapeutic Relevance: Modulating epigenetic enzymes (e.g., histone deacetylase inhibitors, DNA methyltransferase inhibitors) or using nutritional interventions (e.g., folate, B vitamins) to restore youthful epigenetic profiles.

4.1.4. Loss of Proteostasis

Description: The breakdown of the intricate cellular machinery responsible for maintaining the quality, concentration, and localization of proteins, leading to the accumulation of misfolded and aggregated proteins.

Mechanism: Cells employ a robust proteostasis network comprising chaperones (heat shock proteins) that assist in protein folding, and degradation systems: the ubiquitin-proteasome system (UPS) for short-lived or misfolded proteins, and autophagy-lysosomal pathways for bulk degradation and damaged organelles. With age, the efficiency of these systems declines, leading to an imbalance where protein synthesis and folding exceed degradation capacity. This results in the accumulation of toxic protein aggregates.

Contribution to Aging/Disease: Impaired proteostasis is a central feature of neurodegenerative diseases such as Alzheimer’s (amyloid-beta, tau), Parkinson’s (alpha-synuclein), and Huntington’s disease (huntingtin protein), where protein aggregates cause cellular toxicity and neuronal death. It also contributes to sarcopenia and cardiomyopathy.

Therapeutic Relevance: Strategies aim to enhance chaperone activity, boost proteasome function, or stimulate autophagy (e.g., rapamycin, spermidine, caloric restriction mimetics).

4.2. Antagonistic Hallmarks (Compensatory Responses that Become Deleterious)

These hallmarks represent adaptive responses that are initially beneficial but become maladaptive or detrimental over time, contributing to aging pathologies.

4.2.1. Deregulated Nutrient Sensing

Description: The disruption of cellular pathways that sense nutrient availability and regulate metabolism, growth, and repair in response. These pathways include insulin/IGF-1 signaling (IIS), mTOR (mechanistic target of rapamycin), AMPK (AMP-activated protein kinase), and sirtuins.

Mechanism: Under nutrient abundance, IIS and mTOR pathways promote cell growth and proliferation, while suppressing stress resistance and autophagy. Under nutrient scarcity (e.g., caloric restriction), AMPK and sirtuins become activated, promoting catabolic processes like autophagy, DNA repair, and mitochondrial biogenesis, while inhibiting growth. With aging, these pathways often become deregulated, leading to chronic activation of growth-promoting pathways and reduced activation of protective pathways, even in the absence of nutrient excess.

Contribution to Aging/Disease: Deregulated nutrient sensing contributes to metabolic syndrome, type 2 diabetes, obesity, cancer, and cardiovascular disease. For instance, chronic activation of mTOR is associated with impaired autophagy and cellular senescence.

Therapeutic Relevance: Pharmacological interventions (e.g., metformin targeting AMPK, rapamycin targeting mTOR) and lifestyle modifications (e.g., caloric restriction, intermittent fasting) are prime examples of geroscience interventions targeting these pathways.

4.2.2. Mitochondrial Dysfunction

Description: A decline in the efficiency and integrity of mitochondria, the cellular powerhouses.

Mechanism: With age, mitochondria accumulate oxidative damage to their proteins, lipids, and DNA (mtDNA). There’s a decrease in the efficiency of the electron transport chain, leading to reduced ATP production and increased leakage of electrons, generating more ROS. Impaired mitochondrial dynamics (fission/fusion), biogenesis (formation of new mitochondria), and mitophagy (selective removal of damaged mitochondria) further exacerbate the problem. Accumulation of mtDNA mutations is also a significant factor.

Contribution to Aging/Disease: Mitochondrial dysfunction is implicated in a wide range of age-related diseases, including neurodegenerative disorders (e.g., Parkinson’s), cardiovascular diseases, sarcopenia, metabolic syndrome, and kidney disease, due to insufficient energy supply and increased oxidative stress.

Therapeutic Relevance: Strategies include exercise, caloric restriction, antioxidants, and compounds that promote mitochondrial biogenesis (e.g., PGC-1α activators) or enhance mitophagy (e.g., urolithin A).

4.2.3. Cellular Senescence

Description: A stable state of cell cycle arrest, typically induced by various stressors (e.g., telomere attrition, DNA damage, oncogenic activation), where cells remain metabolically active but lose their ability to divide. Senescent cells accumulate in tissues with age.

Mechanism: Senescent cells undergo profound phenotypic changes, including resistance to apoptosis, altered metabolism, and the acquisition of the Senescence-Associated Secretory Phenotype (SASP). SASP involves the secretion of a complex cocktail of pro-inflammatory cytokines, chemokines, growth factors, and proteases into the local tissue microenvironment.

Contribution to Aging/Disease: While senescent cells initially act as a tumor-suppressive mechanism and contribute to wound healing, their chronic accumulation and SASP contribute significantly to chronic low-grade inflammation (‘inflammaging’), extracellular matrix degradation, stem cell dysfunction, and impaired tissue regeneration. They drive pathologies like osteoarthritis, atherosclerosis, idiopathic pulmonary fibrosis, and neurodegeneration.

Therapeutic Relevance: Development of senolytics (drugs that selectively kill senescent cells, e.g., dasatinib+quercetin, fisetin) and senomorphics (drugs that modulate the SASP, e.g., metformin) is a rapidly advancing area in geroscience, showing promise in preclinical and early clinical trials.

4.3. Integrative Hallmarks (Phenotypic Manifestations)

These hallmarks represent the downstream consequences and systemic effects resulting from the accumulation of damage and dysregulation described by the primary and antagonistic hallmarks.

4.3.1. Stem Cell Exhaustion

Description: A progressive decline in the number, function, and regenerative capacity of adult stem cells in various tissues and organs with age.

Mechanism: Stem cells are crucial for tissue repair and homeostasis. Their decline is due to a combination of factors, including accumulated DNA damage, telomere attrition, epigenetic alterations, mitochondrial dysfunction, and exposure to chronic inflammation and senescent cells in their niche. The stem cell niche itself, composed of surrounding cells and extracellular matrix, also ages, becoming less supportive of stem cell function.

Contribution to Aging/Disease: Stem cell exhaustion impairs the regenerative potential of tissues, leading to slower wound healing, muscle wasting (sarcopenia), hematopoietic decline (anemia, impaired immunity), and impaired brain repair (neurogenesis). This contributes to the functional decline of multiple organ systems.

Therapeutic Relevance: Strategies include stimulating endogenous stem cell activity, replenishing stem cell populations (e.g., through transplantation), or rejuvenating the stem cell niche.

4.3.2. Altered Intercellular Communication

Description: Changes in the signaling molecules, receptors, and pathways that mediate communication between cells, tissues, and organs, leading to systemic dysregulation.

Mechanism: This hallmark encompasses several aspects: chronic low-grade inflammation (inflammaging) driven by SASP, pathogen exposure, and gut dysbiosis; changes in immune cell function (immunosenescence) characterized by reduced adaptive immunity and increased innate immunity; dysregulation of endocrine signaling (e.g., insulin resistance, declining growth hormone and sex hormone levels); altered neurotransmission in the nervous system; and changes in the extracellular matrix (ECM) affecting cell-cell interactions and tissue mechanics.

Contribution to Aging/Disease: Impaired intercellular communication underlies numerous age-related diseases. Inflammaging contributes to atherosclerosis, neurodegeneration, sarcopenia, and cancer. Immunosenescence increases susceptibility to infections and reduces vaccine efficacy. Endocrine changes contribute to metabolic disorders and bone loss.

Therapeutic Relevance: Targeting chronic inflammation, restoring immune balance, and modulating endocrine pathways are key areas. For instance, drugs like rapamycin and metformin can impact multiple aspects of intercellular communication.

4.4. Emerging and Proposed Hallmarks

Beyond the original nine, research continues to refine and expand the list, highlighting the dynamic nature of geroscience.

4.4.1. Chronic Inflammation (Inflammaging)

Description: While closely linked to altered intercellular communication, chronic low-grade inflammation, or ‘inflammaging,’ is increasingly recognized as a distinct and pervasive driver of aging (Franceschi et al., 2018). It is characterized by persistently elevated levels of pro-inflammatory cytokines (e.g., IL-6, TNF-α, CRP) in the absence of overt infection.

Mechanism: Sources include senescent cells (SASP), gut dysbiosis (leaky gut allowing microbial products into circulation), accumulation of cellular debris, persistent viral infections (e.g., cytomegalovirus), and sterile inflammation from metabolic stress. This persistent inflammatory state leads to tissue damage and systemic dysfunction.

Contribution to Aging/Disease: Inflammaging is a common underlying factor in cardiovascular disease, type 2 diabetes, neurodegenerative diseases, sarcopenia, frailty, and cancer. It impairs immune function and exacerbates other hallmarks.

Therapeutic Relevance: Anti-inflammatory drugs, senolytics (to remove SASP-producing cells), probiotics, and dietary interventions.

4.4.2. Microbiome Alterations

Description: Significant changes in the composition and function of the commensal microbial communities (e.g., gut, skin, oral) with age.

Mechanism: The gut microbiome, particularly, undergoes dysbiosis with aging, characterized by reduced diversity, loss of beneficial bacteria (e.g., Bifidobacterium, Faecalibacterium prausnitzii), and an increase in potentially pathogenic species. This dysbiosis can impair gut barrier function (‘leaky gut’), leading to translocation of microbial products (e.g., LPS) into the bloodstream, triggering systemic inflammation.

Contribution to Aging/Disease: Gut dysbiosis contributes to inflammaging, metabolic dysfunction, impaired immune responses, and may influence neurodegenerative processes through the gut-brain axis. It affects nutrient absorption and host metabolism.

Therapeutic Relevance: Probiotics, prebiotics, dietary interventions, and even fecal microbiota transplantation are being investigated to restore a youthful microbiome composition.

4.4.3. Macromolecular Aggregation (beyond proteostasis)

Description: While partially covered by loss of proteostasis, specific and persistent aggregation of macromolecules, often involving lipids and carbohydrates, can be considered a distinct hallmark. This includes the accumulation of advanced glycation end products (AGEs) and lipofuscin.

Mechanism: AGEs form when sugars react non-enzymatically with proteins or lipids, forming irreversible cross-links that stiffen tissues and promote inflammation. Lipofuscin, or ‘age pigment,’ is an indigestible aggregate of oxidized proteins and lipids that accumulates in lysosomes, particularly in post-mitotic cells like neurons and cardiomyocytes, contributing to lysosomal dysfunction.

Contribution to Aging/Disease: AGEs contribute to arterial stiffness, kidney disease, and neurodegenerative conditions. Lipofuscin accumulation impairs lysosomal function and cellular viability.

Therapeutic Relevance: Reducing sugar intake, developing AGE inhibitors, and finding ways to promote lysosomal clearance of lipofuscin.

4.4.4. Changes in Lipid Metabolism

Description: Age-related dysregulation of lipid synthesis, transport, and catabolism, leading to ectopic lipid accumulation (lipotoxicity) and altered lipid signaling.

Mechanism: As individuals age, changes occur in adipose tissue distribution, often leading to visceral fat accumulation. There is also impaired lipid oxidation, increased de novo lipogenesis, and altered lipoprotein profiles. These changes can result in accumulation of harmful lipid species (e.g., ceramides, diacylglycerols) in non-adipose tissues like muscle, liver, and pancreas.

Contribution to Aging/Disease: Lipotoxicity contributes to insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, and cardiomyopathy, accelerating cellular dysfunction and inflammation.

Therapeutic Relevance: Dietary interventions, exercise, and lipid-lowering drugs (e.g., statins, fibrates) are relevant.

4.4.5. Loss of Adaptability/Resilience

Description: The overarching decline in an organism’s capacity to maintain homeostasis and effectively respond to various stressors (e.g., infection, injury, environmental changes) with increasing age.

Mechanism: This is an integrative hallmark resulting from the cumulative impact of all other hallmarks. Declining stem cell function, impaired immune response, deregulated nutrient sensing, and chronic inflammation all contribute to a reduced ‘physiological reserve.’ This means that older individuals have a narrower homeostatic range and are more susceptible to decompensation under stress.

Contribution to Aging/Disease: Manifests as increased frailty, slower recovery from illness or injury, and heightened vulnerability to adverse outcomes following acute stressors.

Therapeutic Relevance: Any intervention that targets the upstream hallmarks indirectly enhances resilience. This is the ultimate goal of healthspan extension.

These hallmarks provide a robust framework for geroscience research, guiding the identification of molecular targets and the development of interventions designed to modulate the aging process itself.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Interdisciplinary Nature of Geroscience

The profound complexity of aging necessitates a deeply interdisciplinary approach, drawing expertise from a wide array of scientific fields. Geroscience thrives at the convergence of traditional disciplines, integrating diverse methodologies and perspectives to construct a holistic understanding of how and why organisms age. This collaborative synergy is not merely advantageous but absolutely essential for translating fundamental discoveries into effective healthspan-extending interventions.

5.1. Core Contributing Disciplines

• Genetics and Genomics: Provides the blueprint for understanding hereditary influences on longevity and disease susceptibility. Techniques such as genome-wide association studies (GWAS) identify genetic variants linked to aging traits, while advanced genomic sequencing, including single-cell genomics, reveals age-associated changes in gene expression and epigenetic landscapes. Gene editing technologies (e.g., CRISPR-Cas9) enable precise manipulation of longevity-related genes in model organisms to validate their roles in aging pathways.

• Cell Biology: Forms the bedrock of geroscience, investigating fundamental cellular processes (e.g., DNA repair, protein synthesis, mitochondrial function, autophagy, cell cycle regulation) and their alterations with age. Researchers utilize sophisticated imaging techniques, cell culture models, and organoids to visualize and analyze cellular senescence, stem cell behavior, and organelle dynamics in real-time. Single-cell technologies allow for the identification of heterogeneous aging phenotypes within cell populations.

• Biochemistry and Pharmacology: Focuses on the molecular interactions and metabolic pathways affected by aging. Biochemists elucidate how proteins, lipids, and carbohydrates are altered with age, impacting cellular function. Pharmacologists leverage this understanding to discover and develop small molecules, biologics, and repurposed drugs (geroprotectors) that target specific aging mechanisms. High-throughput screening platforms are employed to identify compounds that modulate nutrient-sensing pathways, clear senescent cells, or enhance proteostasis.

• Epidemiology and Public Health: Examines aging patterns, disease incidence, and risk factors at the population level. Longitudinal studies track large cohorts over decades, providing invaluable data on the interplay between genetic predispositions, lifestyle factors, environmental exposures, and the development of age-related diseases. Public health researchers translate geroscience findings into policy recommendations and public health interventions aimed at promoting healthy aging across diverse populations.

• Immunology: Investigates immunosenescence, the age-related decline in immune system function. This involves understanding why the adaptive immune system becomes less effective (e.g., reduced naive T cell output, impaired vaccine responses) and the innate immune system becomes chronically activated (e.g., inflammaging). Immunologists explore how these changes contribute to increased susceptibility to infections, cancer, and autoimmune conditions in older adults.

• Neuroscience: Addresses age-related cognitive decline and neurodegenerative diseases. Neuroscientists study how aging impacts neuronal plasticity, synaptic function, neurotransmitter systems, and the accumulation of protein aggregates (e.g., amyloid-beta, tau) in the brain. Research also focuses on neuroinflammation, changes in glial cell function, and the potential for neurogenesis in the aging brain.

• Bioinformatics and Data Science: Essential for managing, integrating, and interpreting the vast datasets generated in geroscience, from multi-omics data to large-scale clinical trial results. Advanced computational algorithms, machine learning, and artificial intelligence are used to identify novel biomarkers of aging, predict disease risk, uncover drug targets, and model complex biological networks.

• Evolutionary Biology: Provides the foundational theoretical framework for understanding why aging exists as a biological phenomenon, as discussed earlier with the disposable soma and antagonistic pleiotropy theories. This perspective helps guide research by distinguishing between fundamental aging mechanisms and their downstream consequences.

• Sociology and Ethics: Addresses the broader societal implications of extending healthspan, including issues of equitable access to interventions, potential impacts on workforce and retirement, intergenerational equity, and the ethical considerations surrounding human lifespan modification. These disciplines ensure that scientific advancements are considered within a robust societal and ethical framework.

This collaborative ethos allows geroscience to develop multifaceted strategies that move beyond single-disease approaches, fostering a comprehensive understanding necessary to truly promote healthy aging across the entire lifespan.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Potential to Shift Medical Paradigms

Geroscience holds the profound potential to fundamentally redefine the landscape of medical practice and public health. By directly targeting the foundational biological mechanisms of aging, this paradigm promises to move healthcare from a reactive, disease-centric model to a proactive, healthspan-centric approach. The implications are far-reaching, offering benefits that extend beyond individual health to societal well-being and economic stability.

6.1. Prevent Multiple Diseases Simultaneously (The ‘Longevity Dividend’)

One of the most compelling aspects of geroscience is its capacity to address multiple age-related diseases concurrently. Since aging is the single largest risk factor for conditions like cardiovascular disease, cancer, type 2 diabetes, neurodegeneration, and frailty, intervening in the aging process itself could simultaneously mitigate the risk for all these pathologies. This concept is often referred to as the ‘longevity dividend’ (Olshansky et al., 2006). Instead of treating each disease independently—a costly and often palliative endeavor—geroscience aims for a single therapeutic strategy, or a combination of strategies, that delays or prevents the onset of an entire cluster of diseases. This approach is significantly more efficient and has the potential to yield unprecedented public health benefits, dramatically reducing the incidence of chronic conditions that currently burden individuals and healthcare systems.

6.2. Extend Healthspan and Improve Quality of Life

The primary objective of geroscience is not merely to extend chronological lifespan, but critically, to extend healthspan—the period of life lived in good health, free from significant disease and disability. While an extended lifespan may be a desirable side effect, the emphasis remains on improving the quality of life in later years. Imagine a future where individuals remain physically active, cognitively sharp, and socially engaged well into what is currently considered advanced old age. By delaying the onset of frailty, cognitive impairment, and physical limitations, geroscience interventions aim to empower older adults to maintain independence and contribute meaningfully to society for a longer duration. This focus on functional health aligns with societal aspirations for graceful and dignified aging.

6.3. Reduce Healthcare Burden and Economic Savings

The economic implications of geroscience are monumental. Chronic age-related diseases account for a substantial portion of healthcare expenditures globally. By delaying the onset of these diseases by even a few years, geroscience could lead to massive savings in healthcare costs, potentially in the trillions of dollars annually (Goldman et al., 2013). These savings would stem from reduced hospitalizations, fewer doctor visits, decreased medication use, and less need for long-term care and assisted living facilities. The economic benefits extend beyond healthcare, as a healthier, more productive aging population could continue to contribute to the workforce and economy, reducing dependency ratios and fostering innovation.

6.4. Personalized Medicine Approaches

Geroscience is poised to integrate seamlessly with personalized medicine. Understanding an individual’s unique genetic predispositions, epigenetic profile, lifestyle factors, and specific biological age (as opposed to chronological age) will enable tailored interventions. Multi-omics analyses (genomics, transcriptomics, proteomics, metabolomics) can identify an individual’s specific aging pathways that are most vulnerable or dysregulated. This could lead to precision geroprotective strategies, where interventions are customized based on an individual’s unique ‘aging fingerprint,’ optimizing efficacy and minimizing side effects. For example, specific biomarkers might indicate that one person would benefit most from a senolytic, while another might benefit from an mTOR inhibitor.

6.5. Drug Repurposing and Novel Therapeutics

Geroscience offers a robust framework for both repurposing existing drugs and developing novel therapeutics. Many drugs approved for specific diseases have been found to modulate fundamental aging pathways. For instance, metformin, a common anti-diabetic drug, acts on the AMPK pathway and has shown geroprotective effects in preclinical studies and is currently in clinical trials (TAME trial) for its potential to delay age-related diseases (Barzilai et al., 2016). Rapamycin, an immunosuppressant, targets the mTOR pathway and has consistently extended lifespan and healthspan in model organisms. Beyond repurposing, geroscience is driving the development of entirely new classes of compounds, such as senolytics, which selectively eliminate senescent cells, and senomorphics, which mitigate their harmful secretory profile. The pipeline for novel geroprotective compounds is growing rapidly.

6.6. Policy and Societal Transformation

Beyond clinical practice, geroscience can inform public policy. Recognizing aging as a treatable condition rather than an inevitable decline would necessitate shifts in how healthcare systems are structured, how research is funded, and how society views its older members. Policies could promote preventive interventions based on geroscience insights, invest in research that targets aging mechanisms, and adapt social structures to support a healthier, longer-lived population. This represents a proactive public health approach to aging, fostering a society where individuals can thrive throughout their extended healthspan.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Challenges and Future Directions

Despite its immense promise, geroscience is still a nascent field facing considerable scientific, clinical, ethical, and societal challenges. Overcoming these hurdles will be critical for translating its groundbreaking insights into tangible public health benefits.

7.1. Scientific and Translational Challenges

7.1.1. Complexity and Interconnectedness of Aging Hallmarks

A major challenge lies in the sheer complexity and intricate interconnectedness of the hallmarks of aging. These hallmarks do not operate in isolation; they influence and often exacerbate one another, creating complex feedback loops. For example, mitochondrial dysfunction can lead to increased ROS, causing genomic instability, which in turn can induce cellular senescence, contributing to chronic inflammation (SASP), which further impairs stem cell function. This interconnectedness makes it difficult to identify singular, ‘silver bullet’ interventions. Future research must focus on understanding these complex interactions and developing combination therapies that target multiple hallmarks simultaneously for synergistic effects (Farr et al., 2024).

7.1.2. Individual Variability in Aging Trajectories

Individuals age at vastly different rates due to a combination of genetic predispositions, lifestyle choices, environmental exposures, and social determinants. This biological heterogeneity makes a one-size-fits-all approach to geroscience interventions impractical. The field needs to better account for individual variability, which necessitates the development of sophisticated predictive models and personalized interventions tailored to an individual’s unique biological age and specific aging vulnerabilities. This requires extensive data collection and advanced bioinformatics.

7.1.3. Robust Biomarkers of Biological Age and Intervention Efficacy

Currently, there is a critical need for robust, validated biomarkers that can accurately assess biological age, predict disease risk, and monitor the efficacy of geroprotective interventions. Chronological age is an imperfect proxy for biological aging. While epigenetic clocks (e.g., Horvath clock) show promise, further research is required to develop and validate a panel of integrated biomarkers (including proteomic, metabolomic, inflammatory, and functional markers) that are sensitive to intervention and predict health outcomes. These biomarkers are essential for clinical trials to establish clear endpoints for ‘anti-aging’ therapies.

7.1.4. Clinical Trial Design and Regulatory Hurdles

Designing clinical trials for interventions that target aging is inherently challenging. Aging is a lifelong process, and measuring ‘healthspan extension’ requires long-term studies with appropriate endpoints. Ethical considerations surrounding placebo groups in studies aiming to prevent diseases that manifest decades later also arise. Regulatory agencies (e.g., FDA, EMA) traditionally approve drugs for specific diseases, not for ‘aging’ as a condition. Establishing new regulatory pathways for geroprotectors—drugs that prevent multiple age-related diseases—is crucial. The TAME (Targeting Aging with Metformin) trial is a pioneering effort to gain regulatory acceptance for ‘aging’ as an indication for therapeutic intervention (Barzilai et al., 2016).

7.2. Ethical, Social, and Policy Considerations

7.2.1. Ethical Implications of Lifespan Extension

Interventions that significantly extend healthspan and potentially lifespan raise profound ethical questions. Issues of social equity and access are paramount: if geroprotective therapies become available, how will society ensure equitable access for all, preventing the creation of a two-tiered system where only the wealthy can afford to live longer, healthier lives? There are also philosophical questions about identity, the meaning of life in a longer healthspan, and potential psychological impacts of extended old age.

7.2.2. Societal and Economic Impact

A dramatically healthier and longer-lived population would necessitate significant societal adaptations. This includes reconsidering retirement ages, pension systems, workforce structures, and intergenerational relationships. While a healthier aging population could contribute significantly to the economy, concerns about resource allocation, potential overpopulation, and environmental strain need careful consideration and proactive planning. Public discourse and policy formulation must anticipate these shifts.

7.2.3. Public Acceptance and Misinformation

The public perception of ‘anti-aging’ research is often tainted by misconceptions, sensationalism, and unproven claims. Geroscience needs to clearly distinguish itself from anecdotal ‘anti-aging’ products and effectively communicate its rigorous scientific basis and its focus on healthspan, not just lifespan. Educating the public and policymakers about the scientific rationale and potential benefits of geroscience is crucial for gaining widespread acceptance and support.

7.3. Future Directions for Research and Implementation

7.3.1. Development and Validation of Combination Therapies

Given the interconnected nature of aging hallmarks, future research will increasingly focus on developing and testing combination therapies that target multiple pathways simultaneously. This could involve combining a senolytic with an mTOR inhibitor, or a metabolic modulator with an epigenetic modifier, to achieve synergistic and more comprehensive healthspan benefits.

7.3.2. Leveraging Big Data, AI, and Machine Learning

Advances in bioinformatics and AI will be critical for sifting through vast datasets from multi-omics studies, clinical trials, and epidemiological cohorts. AI can accelerate drug discovery by identifying novel targets, predicting drug efficacy and toxicity, and unraveling complex biological networks of aging. Machine learning algorithms can refine biomarker panels and personalize intervention strategies.

7.3.3. Focus on Preclinical and Early Clinical Translation

Continued robust preclinical research in diverse model organisms (worms, flies, mice) is essential to validate targets and test novel compounds. However, a major push will be to accelerate the translation of promising interventions into well-designed human clinical trials. This requires overcoming regulatory barriers and securing sustained funding for large-scale, long-term studies.

7.3.4. Integrating Geroscience into Standard Medical Education and Practice

To truly shift medical paradigms, geroscience principles need to be integrated into medical education, empowering future physicians to understand aging as a treatable process. Developing clinical guidelines for personalized healthy aging plans based on geroscience insights will be a key step towards mainstreaming this approach.

7.3.5. Global Collaboration and Health Equity

Addressing the global challenge of an aging population requires international collaboration. Sharing data, resources, and expertise across borders will accelerate discovery. Furthermore, ensuring that the benefits of geroscience are accessible to all, regardless of socioeconomic status or geographical location, is a fundamental ethical imperative that must guide future research and policy.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

Geroscience stands at the forefront of a profound scientific revolution, offering a transformative approach to understanding, preventing, and treating the multifactorial challenges posed by aging and its associated diseases. By shifting the focus from disease-specific treatments to directly addressing the fundamental biological processes of aging, geroscience holds unparalleled potential to extend healthspan—the period of life lived free from significant disease and disability—thereby dramatically improving the quality of life for the global aging population. The rigorous exploration of the historical foundations, the extensive scope encompassing molecular, genetic, environmental, and social determinants, and the meticulous dissection of the interconnected hallmarks of aging provide a robust framework for this ambitious endeavor. The inherently interdisciplinary nature of geroscience, drawing expertise from genetics, cell biology, pharmacology, epidemiology, and even sociology, underscores the complexity and systemic reach of its mission.

While significant scientific, clinical, and ethical challenges remain, particularly in validating robust biomarkers, navigating regulatory pathways, and ensuring equitable access, the trajectory of geroscience is clear. Continued, concerted interdisciplinary research, fueled by advancements in big data and artificial intelligence, is essential to unlock the full promise of this field. As we move forward, geroscience is poised not only to revolutionize medicine by preventing multiple chronic conditions simultaneously but also to instigate a fundamental societal paradigm shift, fostering a future where a longer, healthier, and more vibrant old age becomes an achievable reality for all. The ultimate goal is to enable individuals to not merely live longer, but to live better, maintaining their vitality and independence throughout the entirety of their healthspan.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

• Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a Tool to Target Aging. Cell Metabolism, 23(6), 1060–1065.
• Crimmins, E. M., Kim, J. K., & Vazquez, E. (2020). Social Hallmarks of Aging: Suggestions for Geroscience Research. Ageing Research Reviews, 63, 101136.
• Farr, J. N., & Kirkland, J. L. (2024). Targeting Multiple Hallmarks of Mammalian Aging with Combinations of Interventions. Aging (Albany NY), 16(1), 206078.
• Franceschi, C., Garagnani, P., Vitale, M., Capri, M., & Salvioli, S. (2018). Inflammaging: A New Immune-Metabolic View of Aging. Current Opinion in Systems Biology, 10, 122-127.
• Goldman, D. P., Cutler, D. M., Rowe, J. W., Michaud, P. C., Sullivan, J., Peneva, D., & Olshansky, S. J. (2013). Substantial health and economic returns from delayed aging. Health Affairs, 32(10), 1698–1705.
• Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14(10), R115.
• Kirkwood, T. B. L. (1977). Evolution of ageing. Nature, 270, 301–304.
• López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. Cell, 153(6), 1194–1217.
• López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278.
• Medawar, P. B. (1952). An Unsolved Problem of Biology. H. K. Lewis.
• Metchnikoff, É. (1903). The Nature of Man: Studies in Optimistic Philosophy. G.P. Putnam’s Sons.
• National Geroscience Initiative. (n.d.). Overview. Retrieved from geroscience.health
• Olshansky, S. J., Goldman, D. P., Zheng, Y., & Rowe, J. W. (2006). The Longevity Dividend: What Will It Mean for Health and Health Care? The Milbank Quarterly, 84(4), 585–599.
• Pifer, R., & Lopez, R. (2020). Social Hallmarks of Aging: Suggestions for Geroscience Research. Ageing Research Reviews, 63, 101136.
• The Healthy Aging Initiative | Harvard T.H. Chan School of Public Health. (n.d.). More about the initiative. Retrieved from hsph.harvard.edu
• Williams, G. C. (1957). Pleiotropy, Natural Selection, and the Evolution of Senescence. Evolution, 11(4), 398–411.
• Wolfe, C. M., & Williams, M. A. (2018). Revisiting the Evolutionary Theory of Antagonistic Pleiotropy for APOE and Alzheimer’s Disease. Frontiers in Aging Neuroscience, 10, 421.