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Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing ‘disorderliness’ of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular ‘order’ and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.

Heterochronic blood exchange (HBE) has demonstrated that circulating factors restore youthful features to aged tissues. However, the systemic mediators of those rejuvenating effects remain poorly defined. We show here that the beneficial effect of young blood on aged muscle regeneration was diminished when serum was depleted of extracellular vesicles (EVs). Whereas EVs from young animals rejuvenate aged cell bioenergetics and skeletal muscle regeneration, aging shifts EV subpopulation heterogeneity and compromises downstream benefits on recipient cells. Machine learning classifiers revealed that aging shifts the nucleic acid, but not protein, fingerprint of circulating EVs. Alterations in sub-population heterogeneity were accompanied by declines in transcript levels of the pro-longevity protein, α-Klotho, and injection of EVs improved muscle regeneration in a Klotho mRNA-dependent manner. These studies demonstrate that EVs play a key role in the rejuvenating effects of HBE and that Klotho transcripts within EVs phenocopy the effects of young serum on aged skeletal muscle.

Life represents a perpetual contest between two opposing forces, namely, constructive biological forces and destructive physical forces. Biology creates order from chaos; physics creates chaos from order. Through biomolecular interactions, cells perform orchestrated functions such as creating life-sustaining energy, executing specialized tasks, and propagating population succession through self-replication. Yet, these functions are not without consequences and, over time, biomolecules within the cells dissipate energy, make mistakes, and accumulate waste. Aging—characterized by a progressive loss of physiological integrity that leads to impaired function and increased vulnerability to death—arguably begins at that turning point when destructive physical forces start to dominate over constructive biological forces. This time-dependent accumulation of molecular mistakes leads to ever-increasing chaos (Lipsitz & Goldberger, 1992). A chaotic system is characterized by unpredictable behavior that is highly sensitive to initial conditions but can be explained by deterministic laws. As biomolecules within a given cell communicate with each other to perform complex tasks, ‘wear and tear’ of the system results in increased noise and, thus, an impaired information flow—or entropy.In 1948, Claude Shannon mathematically described communication of information over a noisy channel (Shannon, 1948). In this now seminal work, Shannon described entropy as a measure of ‘information’ or uncertainty encoded in a message. The greater the uncertainty, the greater the amount of stored information, or entropy. Since Shannon set the stage for the formation of the novel field of Information Theory, its principles have extended into numerous applications, including language, engineering, and medicine. A decade later, prominent bio-gerontologist, Bernard Strehler, suggested that information theory can help understand whether age-related deterioration is due to ‘the disorganization of stored collection of directions (information)’ or ‘the disruption of information transmitting or decoding machinery’ (Blokh & Stambler, 2017).In this dissertation, we present a series of studies that test the central hypothesis that aging is a result of disordered information at the transcriptomic level, and disruption of the message propagation machinery in individual aging cells. Understanding if and how an aging system preserves certain biological functions may ultimately help researchers develop anti-aging therapeutics that preserve effective biomolecular communication over time.

Abstract To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion—even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as “aging” by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.

Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the great majority of KOA seen clinically, the bulk of our mechanistic understanding of KOA has been derived using surgically induced post-traumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics to elucidate pathogenic mechanisms of age-related KOA in murine model. Protein-level data together with transcriptomic profiling revealed inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of aged cartilage were unique from those in PTOA, with only 1% overlap between the two. At the nexus of aging hallmarks, Advanced Glycation End-Product (AGE)/Receptor for AGE emerged as intrinsically linked to age-related KOA. This pathway was further validated by mass spectrometry. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a key driver of age-related KOA.

Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; input message) and corresponding target genes (TG; output message). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (i.e., channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.Competing Interest StatementThe authors have declared no competing interest.Footnotes* The paper now focuses on skeletal muscle aging. Figure 4 and Supplemental figures have been updated.* https://github.com/sruthi-hub/Aging_information_theory_TMS

Aging is accompanied by a disrupted information flow, which results from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders such as skeletal muscle wasting, or sarcopenia. To estimate the growing ″disorderliness″ of the aging muscle system, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Although the most prominent structural and functional alterations were observed in the oldest old mice (27-29 months), we found that the escalating network entropy reached an inflection point at old age (22-24 months). To probe the potential for restoration of molecular ″order″ and reversal of the sarcopenic phenotype, we overexpressed the longevity protein, α-Klotho. Klotho overexpression modulated genes representing all hallmarks of aging in both old and oldest-old mice. However, whereas Klotho improved strength in old mice, intervention failed to induce a benefit beyond the entropic tipping point. Competing Interest Statement J.H., S.K., and M.F. are employees of Boehringer Ingelheim Pharmaceutical Company. The remaining authors declare no competing interests.

Changing family structures, nuclearization and urbanization are reshaping the socialization and support networks of older adults. Smaller families and migration reduce direct care and engagement opportunities, impacting health and functional ability in the growing aging population. The study explored social networks and perceived social support for older adults in rural and urban Chengalpattu, Tamil Nadu, through 33 in-depth interviews (22 older adults and 11 caregivers). Using the Convoy Model of Social Relations, thematic analysis revealed that immediate close ties, such as spouses and children, provided essential emotional, physical and financial support to maintain functional ability, regardless of the individual's location. The middle circle of the extended family assisted with hospital visits, meals during emergencies and support when the immediate family was absent. The outer circle, comprising non family members and formal caregivers, offered physical, informational, logistical and occasional financial help. Parents of migrated children often receive financial aid and virtual emotional support, whereas extended family or neighbors provide physical assistance when caregivers are absent. In urban areas, work demands and technology use limit in-person family interaction, prompting elders to turn to WhatsApp, gaming apps and online health content to combat loneliness. They also perceived taking care of grandchildren as burdensome. In contrast, rural elders viewed time with children as “medicine” for emotional well-being. Caregivers reported feeling burdened by elder care, which increased the demand for caregiver support groups to reduce emotional strain. Strengthening intergenerational social relationships and promoting healthy, purposeful technology use are key strategies to support functional ability, emotional health and overall well-being in India’s aging population.

Background Social frailty and reduced functional ability are major challenges among older adults in urban slums, yet the mechanisms linking these factors remain poorly understood. Social capital may buffer the effects of social frailty, but evidence is limited in urban slums context. The protocol study hypothesized that higher social capital is associated with lower social frailty and better functional ability among older adults. Methods This protocol employs a convergent-parallel mixed-methods design. The quantitative phase will assess social frailty, social capital, and functional ability (Activities of Daily Living, Instrumental ADL, hand grip strength) among older adults. The qualitative phase will involve in-depth interviews with older adults and their caregivers to explore how older adults living in urban slum settings describe their social relations, social networks, and lived experiences of ageing, and how these networks and social support systems influence their daily activities, wellbeing, and functional independence. Quantitative and qualitative data will be analyzed separately and then integrated to identify pathways through which social capital influence’s functional ability. Discussion The study will provide insights into how social resources and relationships support functional independence in marginalized older adults. Findings will inform development of context-sensitive strategies and interventions aimed at enhancing social support, promoting resilience, and improving wellbeing in urban slum populations.