Ageing Begins in the Stem Cell “Neighbourhood”, Not the Stem Cells Themselves: ARI Pune Study

The study reveals that these neighbouring cells are significantly more vulnerable to ageing-related damage, offering fresh insights into the biology of healthy ageing.

New research suggests that the key to understanding how tissues age and lose their regenerative capacity may lie not within stem cells themselves, but in the health of their surrounding support cells. The study reveals that these neighbouring cells are significantly more vulnerable to ageing-related damage, offering fresh insights into the biology of healthy ageing.

The findings come from researchers at the Agharkar Research Institute (ARI), Pune, an autonomous institute under the Department of Science & Technology (DST), and were published as a cover article in the journal Stem Cell Reports.

Shifting the Focus of Ageing Research

Healthy ageing is a global scientific priority, with researchers seeking ways to delay age-related decline across tissues. Traditionally, ageing has been viewed as a process driven primarily by damage within individual cells. However, this study challenges that view by demonstrating that ageing can originate in the stem cell microenvironment, or “niche,” rather than in the stem cells themselves.

Using the fruit fly Drosophila melanogaster as a model system, scientists examined how reproductive stem cells in the ovary are maintained over time and how ageing disrupts this process.

The Role of Autophagy in Support Cells

The study found a striking contrast between different cell types within the same tissue:

• Germline stem cells—which continuously renew and produce eggs—can function even with very low levels of autophagy, the cell’s internal recycling system.

• In contrast, neighbouring cap cells, which form the stem cell niche, are critically dependent on autophagy for their long-term survival and function.

When key autophagy-related genes such as Atg1, Atg5, or Atg9 were selectively switched off in cap cells, these support cells:

• Accumulated cellular damage

• Lost their structural integrity

• Gradually failed to provide essential maintenance signals to stem cells

Although the stem cells themselves remained intrinsically robust, they were ultimately lost because their supportive microenvironment collapsed.

Niche Failure Triggers Stem Cell Loss

Cap cells play a crucial role by continuously supplying biochemical cues, including Bone Morphogenetic Protein (BMP) signals, which help germline stem cells retain their identity and regenerative capacity.

The researchers showed that:

• Ageing in this system begins with the deterioration of cap cells

• Declining autophagy during midlife weakens BMP signalling

• Stem cells can no longer be maintained once niche support fails

This establishes a direct link between microenvironmental ageing and the loss of tissue regeneration.

A Community-Based View of Ageing

The study highlights ageing as a community-like process, where the fate of stem cells is tightly coupled to the health of neighbouring cells. Different cell types within the same tissue have distinct biological requirements, particularly for autophagy.

By demonstrating that supportive cells can act as early “weak links,” the research underscores the importance of considering entire cellular ecosystems, rather than focusing solely on stem cells, when designing strategies to delay ageing.

Implications Beyond Fruit Flies

The research was led by Kiran Suhas Nilangekar and Dr Bhupendra V. Shravage at the Developmental Biology Group, ARI Pune, placing the institute at the forefront of stem cell niche ageing research.

Although conducted in fruit flies, the core pathways involved—autophagy and stem cell niche signalling—are highly conserved across species. This makes the findings relevant to mammalian tissues such as:

• Intestine

• Skin

• Muscle

where similar niche–stem cell relationships govern tissue maintenance.

New Directions for Healthy Ageing Interventions

The study suggests that protecting or strengthening support cells could indirectly preserve stem cell function and delay age-related tissue decline. This opens new avenues for interventions aimed at:

• Preserving fertility

• Maintaining tissue health

• Slowing the loss of regenerative capacity during ageing

Future research will explore how different cell types balance resilience and fragility within tissues, and whether targeted modulation of autophagy in niche cells can slow ageing-related degeneration.

Publication Link

The full study is available at:https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(25)00316-9