Hallmark 10: Altered Intercellular Communication
What Is Altered Intercellular Communication?
My Father likes to use his hearing aids as an option for selective hearing. When he wants to join the conversation, they’re on, when he wants peace and quiet, they’re either off or not in his ears at all! Jokes aside, over the years the background noise of life can become harder to separate, meaning communication requires more effort as the hearing system ages. This is a good analogy to have in mind when thinking about intracellular communication. While cells don’t have the option of selective hearing, ageing is accompanied by a gradual build-up of biological “background noise” which can make messages between cells harder to interpret and more likely to be misunderstood with age. The once finely tuned system of cell-to-cell communication becomes cluttered with “noise”, namely inflammation and stress signals. This loss of clarity is known as altered intercellular communication, the tenth hallmark of ageing [1].
Intercellular communication is vital for virtually everything our bodies do: regulating immunity, repairing tissues, coordinating hormones, and maintaining balance (homeostasis). When this communication breaks down, the body struggles to maintain stability and ageing accelerates.
How Does It Happen and Why Does It Contribute to Ageing?
Long-range vs short-range communication
Cells don’t work in isolation, they constantly send and receive messages to one another to coordinate repair, growth and metabolism, some communication is exchanged locally, like a passing chat, while others travel far, more like a phone call or a first-class postcard delivered through the bloodstream [2,3].
Long-range communication The brain, nerves and endocrine system release chemical messengers, such as hormones and signalling molecules, into the bloodstream. These travel throughout the body and bind to specific receptors on distant cells, triggering changes in gene activity that affect metabolism, inflammation and repair.
Short-range communication is more local. Neighbouring cells talk directly to each other, tissues release soluble molecules, and cells respond to signals from their immediate surroundings.
With ageing, both systems become noisy. Messages are delayed, distorted or drowned out, so cells no longer respond appropriately.
A noisy environment inside the body: inflammation
One of the biggest sources of biological “noise” is chronic inflammation.
In the original Hallmarks of Ageing framework published in 2013, inflammation was grouped under altered intercellular communication [4]. By 2023, it was recognised as important enough to become its own hallmark — although the two remain deeply interconnected [1[.
As we age:
The immune system becomes less efficient at clearing damaged cells and pathogens
Senescent cells (older cells that no longer divide) accumulate
These senescent cells release a cocktail of inflammatory molecules known as the Senescence-Associated Secretory Phenotype (SASP)
This leads to persistent, low-grade inflammation called inflammaging [5].
Inflammaging raises the “background noise” of the body. Important signals become harder for cells to recognise, while inflammatory messages are repeated too often or too loudly [6]. The result is confused communication that disrupts repair, metabolism and immune balance.
The extracellular matrix: stiff conversations
Cells sit within a supportive “scaffolding” called the extracellular matrix (ECM). With age, long-lasting proteins like collagen can become cross-linked and rigid overall causing whole tissues to become stiff. This stiffening sends biochemical signals that push cells toward inflammation, fibrosis and senescence [7]. Senescent cells, in turn, release more ECM-remodelling enzymes and inflammatory factors, amplifying the cycle. ECM rigidity is now recognised as a driver of ageing, and a potential target for therapies aimed at restoring more youthful tissue environments [8].
When communication breaks down, damage accumulates
When long-range and short-range cellular communication are disrupted by biological noise, particularly chronic inflammation, senescent cell signalling and tissue stiffness, cells stop receiving clear instructions. Long-range signals sent through the bloodstream become diluted or overridden by inflammatory molecules, while short-range signals between neighbouring cells are distorted by a damaged local environment. As a result, cells may respond too weakly, too strongly, or at the wrong time. Over time, this loss of coordinated signalling reduces the body’s ability to maintain homeostasis, allowing damage to accumulate and accelerating functional decline across organs: a central driver of ageing [10].
Brain
Miscommunication between neurons and immune cells in the brain’s microglia leads to chronic inflammation and impaired repair.
Immune system
The immune system becomes both overactive (inflammation) and underactive (reduced pathogen clearance). This confused signalling makes older adults more prone to chronic diseases and slower vaccination responses.
Muscles
Reduced communication from growth and repair pathways slows muscle regeneration and contributes to sarcopenia (muscle loss).
Blood and bone marrow
Ageing stem cells in the bone marrow receive mixed or inhibitory signals, producing fewer healthy blood cells which can weaken immunity.
Metabolic organs
Miscommunication between fat tissue, liver and muscles affects hormone and glucose regulation, contributing to metabolic syndrome and type 2 diabetes.
Can we slow down altered intercellular communication to slow ageing?
This an active area of research! Scientists are exploring several ways to reduce biological “noise” to help cells communicate more clearly again.
Reducing inflammaging
Because chronic inflammation disrupts signalling, many approaches focus on quietening this background noise [11]. Areas under investigation include:
Senolytics, drugs designed to remove senescent (“zombie”) cells
SASP inhibitors, which aim to reduce the harmful inflammatory signals released by these cells
Immune-modulating therapies to restore a more balanced immune response
Autophagy-enhancing strategies, which help cells clear out damaged components more efficiently
Restoring healthier blood signals
The bloodstream carries long-range messages between organs. Some trials are exploring whether:
Reducing pro-ageing factors in the blood (for example through plasma exchange), or mimicking signals found in younger blood might improve tissue function and resilience in humans based on pre-clinical evidence of this [12].
Rejuvenating tissue environments
Cells also respond to the physical properties of their surroundings. Early pre-clinical research suggests that therapies which:
Reduce tissue stiffness
Promote healthier collagen turnover
Activate pathways involved in sensing tissue flexibility
may help restore more youthful cellular behaviour [13].
Lifestyle Approaches to Keep Cellular Communication Clear
While laboratory research advances, everyday actions offer powerful ways to reduce inflammatory noise and support healthier communication networks across the body.
1. Reducing chronic inflammation
Eat a whole-food diet rich in fibre, colourful vegetables and healthy fats
Limit ultra-processed foods and excess sugars
Maintain a healthy body weight
Prioritise good oral health, as gum disease is strongly linked to systemic inflammation
2. Support immune resilience
Aim for regular physical activity - particularly brisk walking and strength training
Get sufficient sleep
Manage stress through mindfulness, yoga, or breathing techniques
3. Enhance metabolic balance
Follow patterns such as time-restricted eating or moderate calorie restriction (if appropriate and medically safe)
Keep alcohol intake moderate
4. Keep tissues flexible
Engage in regular movement and stretching
Avoid long periods of inactivity
Support collagen health with adequate protein, vitamin C and micronutrients
5. Avoid accelerators of tissue ageing
Stop smoking
Protect skin from UV exposure
Minimise exposure to environmental pollutants where possible
In Summary
Altered intercellular communication is an integrative hallmark, one that emerges when earlier hallmarks like DNA damage, mitochondrial decline, senescence and inflammation overwhelm the body’s ability to maintain balance. The result is a noisy internal environment where cells struggle to “hear” and respond correctly but, just as adjusting a hearing aid can restore clarity, the right interventions, both lifestyle and scientific, hold real promise for keeping our cells talking clearly for longer.
References:
[1] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349.
[2] Ullo MF, Case LB. How cells sense and integrate information from different sources. WIREs Mech Dis. 2023 Jul-Aug;15(4):e1604. doi: 10.1002/wsbm.1604. Epub 2023 Feb 13. PMID: 36781396
[3] Caviglia S, Ober EA. Non-conventional protrusions: the diversity of cell interactions at short and long distance. Curr Opin Cell Biol. 2018 Oct;54:106-113. doi: 10.1016/j.ceb.2018.05.013. Epub 2018 Jun 8. PMID: 29890397
[4] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217. doi: 10.1016/j.cell.2013.05.039
[5 ]Li, X., Li, C., Zhang, W. et al. Inflammation and aging: signaling pathways and intervention therapies. Sig Transduct Target Ther 8, 239 (2023). https://doi.org/10.1038/s41392-023-01502-8
[6] Daneshpour H, Youk H. Modeling cell-cell communication for immune systems across space and time. Curr Opin Syst Biol. 2019 Dec;18:44-52. doi: 10.1016/j.coisb.2019.10.008
[7]Sherratt MJ. Age-Related Tissue Stiffening: Cause and Effect. Adv Wound Care (New Rochelle). 2013 Feb;2(1):11-17. doi: 10.1089/wound.2011.0328
[8] Selman M, Pardo A. Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology. Ageing Res Rev. 2021 Sep;70:101393. doi: 10.1016/j.arr.2021.101393
[9] Sun H, Xia T, Ma S, Lv T, Li Y. Intercellular communication is crucial in the regulation of healthy aging via exosomes. Pharmacol Res. 2025 Feb;212:107591. doi: 10.1016/j.phrs.2025.107591
[10] Tokizane K, Imai SI. Inter-organ communication is a critical machinery to regulate metabolism and aging. Trends Endocrinol Metab. 2025 Aug;36(8):756-766. doi: 10.1016/j.tem.2024.11.013
[11] Delrue C, Speeckaert R, Speeckaert MM. Rewinding the Clock: Emerging Pharmacological Strategies for Human Anti-Aging Therapy. Int J Mol Sci. 2025 Sep 25;26(19):9372. doi: 10.3390/ijms26199372
[12]Liu MN, Lan Q, Wu H, Qiu CW. Rejuvenation of young blood on aging organs: Effects, circulating factors, and mechanisms. Heliyon. 2024 Jun 15;10(12):e32652. doi: 10.1016/j.heliyon.2024.e32652
[13] d'Angelo M, Benedetti E, Tupone MG, Catanesi M, Castelli V, Antonosante A, Cimini A. The Role of Stiffness in Cell Reprogramming: A Potential Role for Biomaterials in Inducing Tissue Regeneration. Cells. 2019 Sep 5;8(9):1036. doi: 10.3390/cells8091036
Author: Georgia Pilling
